Novel tetrahydropyridopyrimidine compound or salt thereof

ABSTRACT

A method for inhibiting androgen activity, including administering an effective amount of a tetrahydropyridopyrimidine compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, and a method for treating tumor, including administering an effective amount of a tetrahydropyridopyrimidine compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/203,059, filed Jul. 6, 2016, which is a continuation of U.S. patentapplication Ser. No. 15/023,894, filed Mar. 22, 2016, which is theNational Stage of the International Patent Application No.PCT/JP2015/065425, filed May 28, 2015, the disclosures of which areincorporated herein by reference in their entireties. This applicationclaims priority to Japanese Application Number 2014-111147, filed May29, 2014.

TECHNICAL FIELD

The present invention relates to a novel tetrahydropyridopyrimidinecompound which is useful as a pharmaceutical agent, in particular, ananti-androgen agent, and a salt thereof, and a pharmaceuticalcomposition containing them.

BACKGROUND ART

Prostate cancer is the cancer with the highest incidence in men inwestern countries, and it is the second leading cause of cancer death.In Japan, according to westernization in food preferences and humanpopulation aging, the number of prostate cancer patients also increasesover the years. In general, proliferation of prostate cancer cells isstimulated by androgen. As such, for treatment of unresectableprogressive prostate cancer, patients are treated with surgical orchemical castration, and/or administration of an anti-androgen agentso-called androgen deprivation therapy. According to surgical orchemical castration, level of androgen circulating in human body islowered so that the activity of an androgen receptor (it may be referredto as AR hereinbelow) is lowered. As the anti-androgen agent isadministered, the binding of androgen to AR is inhibited, yielding lowerAR activity. Those therapies are very effective for early stagetreatment of most patients. However, cancer recurrence occurs withinseveral years. Such recurrent prostate cancer is referred to ascastration resistant prostate cancer (CRPC).

As a cause of castration resistant prostate cancer, amplification andoverexpression of the AR gene have been confirmed and reported(Non-Patent Literatures 1 and 2). As a result of overexpression of AR,castration resistant prostate cancer exhibits high sensitivity even forandrogen at an ultra-low concentration, which is caused by castrationtreatment. Namely, according to overexpression of AR, AR is activated tocause cancer proliferation. AR mutation has been also confirmed andreported as a cause of castration resistant prostate cancer (Non-PatentLiteratures 3 to 5). According to a mutation in AR, estrogen or ananti-androgen agent itself, which is currently used, can function as anAR agonist, in addition to androgen.

Bicalutamide is the most generally used anti-androgen agent, andexhibits an inhibitory effect in hormone-sensitive prostate cancer as anantagonist for AR. However, the anti-androgen agent includingbicalutamide, which is used for androgen deprivation therapy, has noeffectiveness against castration resistant prostate cancer. The mainreason is that, as AR is overexpressed in castration resistant prostatecancer, the AR antagonist activity is not fully exhibited and the ARagonist activity is shown (Non-Patent Literatures 6 and 7). As such, forinhibition of overexpressed AR in castration resistant prostate cancer,an anti-androgen agent having a more potent AR antagonist activity thana currently used anti-androgen agent and not having an AR agonistactivity is needed. Furthermore, as the anti-androgen agent also has aneffect of reducing AR expression, it can be a more effective therapeuticagent for castration resistant prostate cancer.

In a related art, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine has beenreported as an inhibitor for vanilloid receptor 1 (VR1) (PatentLiteratures 1 to 3). In Patent Literature 1, a bicycloheteroarylaminecompound useful for treatment of pain, inflammatory hyperalgesia,overactive bladder, and urinary incontinence based on inhibition of VR1receptor is disclosed. Furthermore, in Patent Literatures 2 and 3, abicycloheteroarylamine compound useful for treatment of inflammatorypain, for example, is disclosed, and an experimental data for thermalhyperalgeia is described. However, a compound having cyano benzene atposition 7 of the 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine has not beenreported in any one of those Patent Literatures 1 to 3. In addition,there are no descriptions regarding the data relating to an anti-tumoreffect, and the AR antagonist activity or the activity of reducing ARexpression is not described at all.

CITATION LIST Patent Literature

-   Patent Literature 1: WO 2006/062981-   Patent Literature 2: WO 2005/066171-   Patent Literature 3: WO 2006/118598

Non-Patent Literature

-   Non-Patent Literature 1: Koivisto P et al., “Androgen receptor gene    amplification: a possible molecular mechanism for androgen    deprivation therapy failure in prostate cancer”, Cancer Res 57:    314-319, 1997-   Non-Patent Literature 2: Gregory C W et al., “Androgen receptor    stabilization in recurrent prostate cancer is associated with    hypersensitivity to low androgen”, Cancer Res 61: 2892-2898, 2001-   Non-Patent Literature 3: Taplin M E et al., “Mutation of the    androgen-receptor gene in metastatic androgen-independent prostate    cancer”, N Engl J Med 332: 1393-1398, 1995-   Non-Patent Literature 4: Zhao X Y et al., “Glucocorticoids can    promote androgen-independent growth of prostate cancer cells through    a mutated androgen receptor”, Nat Med 6: 703-706, 2000-   Non-Patent Literature 5: Tan J et al., “Dehydroepiandrosterone    activates mutant androgen receptors expressed in the    androgen-dependent human prostate cancer xenograft CWR22 and LNCaP    cells”, Mol Endocrinol 11: 450-459, 1997-   Non-Patent Literature 6: Charlie D Chen et al., “Molecular    determinants of resistance to antiandrogen therapy”, Nature Medicine    10:33-39, 2004-   Non-Patent Literature 7: Takahito Hara et al., “Novel Mutations of    Androgen Receptor: A Possible Mechanism of Bicalutamide Withdrawal    Syndrome”, Cancer Res 63: 149-153, 2003

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention provide sa novel tetrahydropyridopyrimidinecompound, which has a stronger antagonist activity for AR overexpressedin castration resistant prostate cancer than a currently prescribedanti-androgen agent such as bicalutamide, does not exhibit an agonisticactivity for AR, and has an activity of lowering AR expression amount,or a pharmaceutically acceptable salt thereof.

Means for Solving the Problems

As a result of intensive studies, the inventors of the present inventionfound a novel compound group having5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine as a basic structure, a grouprepresented by —NHR at position 4, and cyanobenzene at position 7. Thecompound group has an antagonist activity but no agonist activity forAR, and in addition to effectiveness for cells in which AR is expressed,it has a potent effect of inhibiting cell proliferation for cells inwhich AR is overexpressed. Furthermore, the compound group has, inaddition to the antagonist activity for AR, an activity of lowering ARexpression, and it exhibits an anti-tumor effect in a cancer-bearingmouse model with castration resistant prostate cancer. As such, theinventors of the present invention found that the compound group iseffective as a pharmaceutical agent for treating cancer, and the presentinvention is completed accordingly.

Accordingly, the present invention provides the following [1] to [22].

[1] A tetrahydropyridopyrimidine compound represented by the followingformula (I):

[in the formula,X represents a halogen atom or a halogeno-C₁₋₃ alkyl group;R represents a C₆₋₁₄ aryl group which is substituted with R¹ and may besubstituted simultaneously with R², or a 5- or 6-membered heteroarylgroup which is substituted with R¹ and may be substituted simultaneouslywith R²;R¹ represents a hydrogen atom, a phenyl group, a hydroxy-C₁₋₆ alkylgroup, a hydroxy-C₃₋₇ cycloalkyl group, a C₁₋₆ alkoxy group which may besubstituted with Ra, a C₃₋₇ cycloalkylaminosulfonyl group, a 3- to7-membered monocyclic heterocycloalkylsulfonyl group, a halogeno-C₁₋₃alkoxycarbonylamino group, a halogeno-C₁₋₃ alkylcarbonylamino group, a3- to 7-membered monocyclic heterocycloalkanecarbonyl group substitutedwith a hydroxy-C₁₋₆ alkyl group, or —(CH₂)_(n)—C(═O)—NHRf;R² represents a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkylgroup;Ra represents a C₁₋₆ alkylpyrazolyl group, a triazolyl group, atetrazolyl group, or a C₁₋₆ alkylsulfonylpiperazinyl group;Rf represents a halogeno-C₁₋₃ alkyl group, a hydroxy-C₁₋₆ alkyl group, ahydroxy-C₃₋₇ cycloalkyl group, a hydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkylgroup, or a C₁₋₆ alkyl group substituted with Rfa;Rfa represents a C₁₋₆ alkylpyrazolyl group, a halogeno-C₁₋₃alkylthiazolyl group, an oxadiazolyl group, or a halogeno-C₁₋₃alkyloxadiazolyl group; andn represents an integer of from 0 to 3]or a pharmaceutically acceptable salt thereof.[2] The compound according to [1] or a pharmaceutically acceptable saltthereof, wherein X is a chlorine atom, a bromine atom, or atrifluoromethyl group.[3] The compound according to [1] or [2] or a pharmaceuticallyacceptable salt thereof, wherein n is 0 or 1.[4] The compound according to any one of [1] to [3] or apharmaceutically acceptable salt thereof, wherein R is selected from thegroup consisting of the following groups:

[5] The compound according to any one of [1] to [4] or apharmaceutically acceptable salt thereof, whereinR¹ is a hydrogen atom, a phenyl group, a hydroxy-ethyl group, ahydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, a methoxy group, an isopropoxy group, anethoxy group substituted with a methylpyrazolyl group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, an n-propoxy group substituted with amethylsulfonylpiperazinyl group, a cyclopropylaminosulfonyl group, a1,4-oxazepanylsulfonyl group, a 2,2,2-trifluoroethoxycarbonylaminogroup, a 2,2,2-trifluoroethylcarbonylamino group, a piperidinecarbonylgroup substituted with a hydroxy-isopropyl group, or—(CH₂)_(n)—C(═O)—NHRf;Rf is a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a hydroxycyclohexyl group, ahydroxycyclopropylmethyl group, a methyl group substituted with atrifluoromethylthiazolyl group, an ethyl group substituted with amethylthiazolyl group, an ethyl group substituted with an oxadiazolylgroup, or an ethyl group substituted with a trifluoromethyloxazolylgroup; andn is 0 or 1.[6] The compound according to any one of [1] to [5] or apharmaceutically acceptable salt thereof, wherein R is selected from thegroup consisting of the following groups:

(in the formula, R¹ is a hydrogen atom);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a methyl group substituted with Rfa or an ethyl group substitutedwith Rfa,Rfa is a methylpyrazolyl group or an oxadiazolyl group, andn is 0);

(in the formula,R¹ is a phenyl group, a hydroxy-ethyl group, a hydroxy-isopropyl group,a methoxy group, an isopropoxy group, an ethoxy group substituted with amethylpyrazolyl group, or an n-propoxy group substituted with amethylsulfonylpiperazinyl group);

(in the formula,R¹ is a hydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, an isopropoxy group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, a cyclopropylaminosulfonyl group, a2,2,2-trifluoroethoxycarbonylamino group, a2,2,2-trifluoroethylcarbonylamino group, or —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a fluorine atom, or a chlorine atom,Rf is a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a methylgroup substituted with Rfa, or an ethyl group substituted with Rfa;Rfa is a trifluoromethylthiazolyl group, an oxadiazolyl group, or atrifluoromethyloxadiazolyl group, andn is 0 or 1);

(in the formula,R¹ is a hydroxy-isopropyl group, a 1,4-oxazepanylsulfonyl group, or—(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom or a trifluoromethyl group,Rf is a 2,2,2-trifluoroethyl group or an ethyl group substituted withRfa,Rfa is an oxadiazolyl group, andn is 0);

(in the formula,R¹ is a hydroxy-isopropyl group or —(CH₂)_(n)—C(═O)—NHRf,Rf is a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a hydroxycyclohexyl group, ahydroxycyclopropylmethyl group, andn is 0);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a hydroxy-2-methylpropyl group, andn is 0);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a hydroxy-2-methylpropyl group, andn is 0);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a 2,2,2-trifluoroethyl group, andn is 0);

(in the formula,R¹ is a piperidinecarbonyl group substituted with a hydroxy-isopropylgroup; and

(in the formula,R¹ is a piperidinecarbonyl group substituted with a hydroxy-isopropylgroup).[7] The compound according to any one of [1] to [5] or apharmaceutically acceptable salt thereof, whereinX is a chlorine atom, a bromine atom, or a trifluoromethyl group; andR is selected from the group consisting of the following groups:

R¹ is a hydrogen atom, a phenyl group, a hydroxy-C₁₋₄ alkyl group, ahydroxy-C₃₋₅ cycloalkyl group, a C₁₋₄ alkoxy group which may besubstituted with Ra, a C₃₋₅ cycloalkylaminosulfonyl group, a 7-memberedmonocyclic heterocycloalkylsulfonyl group, a fluoro-C₁₋₃alkoxycarbonylamino group, a fluoro-C₁₋₃ alkylcarbonylamino group, a6-membered monocyclic heterocycloalkanecarbonyl group substituted with ahydroxy-C₁₋₄ alkyl group, or —(CH₂)_(n)—C(═O)—NHRf;R² is a hydrogen atom, a fluorine atom, a chlorine atom, or atrifluoromethyl group;Ra is a C₁₋₄ alkylpyrazolyl group, a triazolyl group, a tetrazolylgroup, or a C₁₋₄ alkylsulfonylpiperazinyl group;Rf is a fluoro-C₁₋₃ alkyl group, a hydroxy-C₁₋₄ alkyl group, ahydroxy-C₃₋₅ cycloalkyl group, a hydroxy-C₃₋₅ cycloalkyl-C₁₋₄ alkylgroup, or a C₁₋₄ alkyl group substituted with Rfa;Rfa is a C₁₋₄ alkylpyrazolyl group, a fluoro-C₁₋₃ alkylthiazolyl group,an oxadiazolyl group, or a fluoro-C₁ 3 alkyloxadiazolyl group; andn is 0 or 1.[8] The compound according to [7] or a pharmaceutically acceptable saltthereof, whereinX is a chlorine atom, a bromine atom, or a trifluoromethyl group; andR is selected from the group consisting of the following groups:

R¹ is a hydrogen atom, a phenyl group, a hydroxy-ethyl group, ahydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, a methoxy group, an isopropoxy group, anethoxy group substituted with a methylpyrazolyl group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, an n-propoxy group substituted with amethylsulfonylpiperazinyl group, a cyclopropylaminosulfonyl group, a1,4-oxazepanylsulfonyl group, a 2,2,2-trifluoroethoxycarbonylaminogroup, a 2,2,2-trifluoroethylcarbonylamino group, a piperidinecarbonylgroup substituted with a hydroxy-isopropyl group, or—(CH₂)_(n)—C(═O)—NHRf;R² is a hydrogen atom, a fluorine atom, a chlorine atom, or atrifluoromethyl group;Rf is a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a hydroxycyclohexyl group, ahydroxycyclopropylmethyl group, a methyl group substituted with atrifluoromethylthiazolyl group, an ethyl group substituted with amethylthiazolyl group, an ethyl group substituted with an oxadiazolylgroup, or an ethyl group substituted with a trifluoromethyl group; andn is 0 or 1.[9] The compound according to [8] or a pharmaceutically acceptable saltthereof, whereinX is a chlorine atom or a trifluoromethyl group; andR is selected from the group consisting of the following groups:

R¹ is a hydrogen atom, a hydroxy-isopropyl group, an isopropoxy group, a2-methylpropoxy group substituted with a tetrazolyl group, an n-propoxygroup substituted with a methylsulfonylpiperazinyl group, a1,4-oxazepanylsulfonyl group, a piperidinecarbonyl group substitutedwith a hydroxy-isopropyl group, or —(CH₂)_(n)—C(═O)—NHRf;R² is a hydrogen atom or a fluorine atom;Rf is a 2,2,2-trifluoroethyl group, a hydroxy-2-methylpropyl group, amethyl group substituted with a trifluoromethylthiazolyl group, an ethylgroup substituted with an oxadiazolyl group, or an ethyl groupsubstituted with a trifluoromethyloxadiazolyl group; andn is 0.

The compound according to [1] or a pharmaceutically acceptable saltthereof, which is selected from the group consisting of the followingcompounds (1) to (19):

-   (1)    4-(4-((1,2,4-thiadiazol-5-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (2)    4-(4-((4-isopropoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (3)    4-(4-((6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (4)    2-chloro-4-(4-((6-(2-hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)benzonitrile;-   (5)    4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (6)    2-chloro-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)benzonitrile;-   (7)    4-(4-((6-(2-hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (8)    6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8,-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide;-   (9)    4-(4-((6-isopropoxypyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (10)    4-(4-((6-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (11)    4-(4-((5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (12)    4-(4-((4-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (13)    4-(4-((5-((1,4-oxazepan-4-yl)sulfonyl)thiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)-2-(trifluoromethyl)benzonitrile;-   (14)    6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyridazine-3-carboxamide;-   (15)    2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyrimidine-5-carboxamide;-   (16)    6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl)nicotinamide;-   (17)    (R)—N-(1-(1,3,4-oxadiazol-2-yl)ethyl)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinamide;-   (18)    (R)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethyl)nicotinamide;    and-   (19)    4-(4-((5-(4-(2-hydroxypropan-2-yl)piperidin-1-carbonyl)oxazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile.    [11] An anti-androgen agent comprising, as an active ingredient, the    tetrahydropyridopyrimidine compound according to any one of [1] to    [10] or a pharmaceutically acceptable salt thereof.    [12] An anti-tumor agent comprising, as an active ingredient, the    tetrahydropyridopyrimidine compound according to any one of [1] to    [10] or a pharmaceutically acceptable salt thereof.    [13] A pharmaceutical agent comprising, as an active ingredient, the    tetrahydropyridopyrimidine compound according to any one of [1] to    [10] or a pharmaceutically acceptable salt thereof.    [14] A pharmaceutical composition comprising the    tetrahydropyridopyrimidine compound according to any one of [1] to    [10] or a pharmaceutically acceptable salt thereof, and a    pharmaceutically acceptable carrier.    [15] Use of the tetrahydropyridopyrimidine compound according to any    one of [1] to [10] or a pharmaceutically acceptable salt thereof for    producing an anti-androgen agent.    [16] Use of the tetrahydropyridopyrimidine compound according to any    one of [1] to [10] or a pharmaceutically acceptable salt thereof for    producing an anti-tumor agent.    [17] Use of the tetrahydropyridopyrimidine compound according to any    one of [1] to [10] or a pharmaceutically acceptable salt thereof for    producing a pharmaceutical agent.    [18] The tetrahydropyridopyrimidine compound according to any one of    [1] to [10] or a pharmaceutically acceptable salt thereof for use in    inhibiting androgen activity.    [19] The tetrahydropyridopyrimidine compound according to any one of    [1] to [10] or a pharmaceutically acceptable salt thereof for use in    treating tumor.    [20] The tetrahydropyridopyrimidine compound according to any one of    [1] to [10] or a pharmaceutically acceptable salt thereof for use as    a pharmaceutical agent.    [21] A method for inhibiting androgen activity, comprising    administering an effective amount of the tetrahydropyridopyrimidine    compound according to any one of [1] to [10] or a pharmaceutically    acceptable salt thereof to a subject in need thereof.    [22] A method for treating tumor, comprising administering an    effective amount of the tetrahydropyridopyrimidine compound    according to any one of [1] to [10] or a pharmaceutically acceptable    salt thereof to a subject in need thereof.

Effects of the Invention

The novel tetrahydropyridopyrimidine compound of the present inventionor a salt thereof exhibits an antagonist activity against an androgenreceptor (AR), and is effective for a disorder related with ARactivation. Examples of a disorder related with AR activation includetumor, metastatic bone disease, prostatic hyperplasia, acne vulgaris,seborrhea, hypertrichosis, androgenetic alopecia, precocious puberty,and virillizing syndrome. Examples of the tumor include prostate cancer,breast cancer, ovarian cancer, bladder cancer, uterine cancer,pancreatic cancer, and hepatocellular cancer.

DESCRIPTION OF EMBODIMENTS

As described herein, examples of the “halogen atom” include a fluorineatom, a chlorine atom, a bromine atom, and an iodine atom.

As described herein, the “C₁₋₆ alkyl group” indicates a linear orbranched alkyl group having 1 to 6 carbon groups, and examples thereofinclude a methyl group, an ethyl group, an n-propyl group, an isopropylgroup, an n-butyl group, a 2-methylpropyl group, a sec-butyl group, atert-butyl group, an n-pentyl group, an isopentyl group, a tert-pentylgroup, a neopentyl group, an n-hexyl group, and a texyl group.Furthermore, as described herein, the “C₁₋₄ alkyl group” and “C₁₋₃ alkylgroup” each indicates, among the aforementioned “C₁₋₆ alkyl group”, analkyl group having 1 to 4 carbon atoms or 1 to 3 carbon atoms.

As described herein, the “halogeno-C₁₋₃ alkyl group” indicates theaforementioned C₁₋₃ alkyl group which is substituted with 1 to 7 halogenatoms that are described above. Examples of the “halogeno-C₁₋₃ alkylgroup” include a fluoro-C₁₋₃ alkyl group and a chloro-C₁₋₃ alkyl groupsuch as a fluoromethyl group, a difluoromethyl group, a trifluoromethylgroup, a trichloromethyl group, a 2-fluoroethyl group, a2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a2,2,2-trichloroethyl group, a monofluoro-n-propyl group, aperfluoro-n-propyl group, and a perfluoroisopropyl group.

As described herein, the “C₆₋₁₄ aryl group” indicates an aryl grouphaving 6 to 14 carbon atoms, and examples thereof include a phenylgroup, a naphthyl group, an antracenyl group, a phenanthryl group, and afluorenyl group.

As described herein, the “heteroaryl group” indicates a monocyclic orpolycyclic group having aromaticity which has 1 to 4 hetero atomsselected from of the group consisting of oxygen, nitrogen, and sulfur.Examples of the heteroaryl group include a furyl group, a thienyl group,a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a diazolylgroup, a triazolyl group, a tetrazolyl group, an oxazolyl group, anoxadiazolyl group, a triazinyl group, a thiazolyl group, a thiadiazolylgroup, an isooxazolyl group, an isothiazolyl group, a pyridinyl group, apyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolylgroup, a quinolyl group, an isoquinolyl group, a benzo[b]thienyl group,a benzimidazolyl group, a benzothiazolyl group, and a benzoxazolylgroup.

As described herein, the “hydroxy-C₁₋₆ alkyl group” indicates theaforementioned C₁₋₆ alkyl group which is substituted with 1 to 3hydroxyl groups. Examples of the “hydroxy-C₁₋₆ alkyl group” include ahydroxymethyl group, a 1-hydroxyethyl group, a 1,2-dihydroxyethyl group,a 1-hydroxypropyl group, a 1,2-dihydroxypropyl group, a1,2,3-trihydroxypropyl group, a 1-hydroxybutyl group, a2-hydroxypropan-2-yl group, and a 2-hydroxy-2-methylpropyl group.

As described herein, the “C₃₋₇ cycloalkyl group” indicates a cyclicalkyl group having 3 to 7 carbon atoms, and examples thereof include acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, and a cycloheptyl group.

As described herein, the “hydroxy-C₃₋₇ cycloalkyl group” indicates theaforementioned C₃₋₇ cycloalkyl group which is substituted with 1 to 3hydroxyl groups. Examples of the “hydroxy-C₃₋₇ cycloalkyl group” includea 1-hydroxycyclopropyl group, a 2-hydroxycyclopropyl group, a1,2-dihydroxycyclopropyl group, a 1,2,3-trihydroxycyclopropyl group, a1-hydroxycyclobutyl group, a 1-hydroxycyclopentyl group, a1-hydroxycyclohexyl group, and a 4-hydroxycyclohexyl group.

As described herein, the “C₁₋₆ alkoxy group” indicates a linear orbranched alkoxy group having 1 to 6 carbon groups, and examples thereofinclude a methoxy group, an ethoxy group, an n-propoxy group, anisopropoxy group, an n-butoxy group, a 2-methylpropoxy group (isobutoxygroup), sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, anisopentyloxy group, a tert-pentyloxy group, a neopentyloxy group, ann-hexyloxy group, and a texyloxy group. Furthermore, as describedherein, the “C₁₋₄ alkoxy group” and “C₁₋₃ alkoxy group” each indicates,among the aforementioned “C₁₋₆ alkoxy group”, an alkoxy group having 1to 4 carbon atoms or 1 to 3 carbon atoms.

As described herein, the “halogeno-C₁₋₃ alkoxy group” indicates theaforementioned C₁₋₃ alkoxy group which is substituted with 1 to 7halogen atoms that are described above. Examples of the “halogeno-C₁₋₃alkoxy group” include a fluoro-C₁₋₃ alkoxy group and a chloro-C₁₋₃alkoxy group such as a fluoromethoxy group, a difluoromethoxy group, atrifluoromethoxy group, a trichloromethoxy group, a 2-fluoroethoxygroup, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a2,2,2-trichloroethoxy group, a monofluoro-n-propoxy group, aperfluoro-n-propoxy group, and a perfluoroisopropoxy group.

As described herein, the “C₃₋₇ cycloalkylaminosulfonyl group” indicatesa sulfonyl group having an amino group substituted with one C₃₋₇cycloalkyl group described above. Examples of the “C₃₋₇cycloalkylaminosulfonyl group” include a cyclopropylaminosulfonyl group,a cyclobutylaminosulfonyl group, and a cyclopentylaminosulfonyl group.

As described herein, the “heterocycloalkyl group” indicates a 3- to7-membered monocyclic alkyl group which has, instead of a carbon atom, 1to 3 hetero atoms selected from the group consisting of oxygen,nitrogen, and sulfur. Examples thereof include an aziridinyl group, anazetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, athiazolidinyl group, a tetrahydrofuranyl group, a tetrahydrothiophenylgroup, a piperidinyl group, a piperazinyl group, a morpholino group, athiomorpholino group, an oxazinanyl group, a thiazinanyl group, anazepanyl group, a diazepanyl group, and an oxazepanyl group.

As described herein, the “heterocycloalkylsulfonyl group” indicates asulfonyl group substituted with the aforementioned heterocycloalkylgroup. Examples of the “heterocycloalkylsulfonyl group” include apiperidin-1-ylsulfonyl group, a morpholinosulfonyl group, a1,4-thiazepan-4-ylsulfonyl group, and a 1,4-oxazepanylsulfonyl group.

As described herein, the “halogeno-C₁₋₃ alkoxycarbonylamino group”indicates an amino group which is substituted with one halogeno-C₁₋₃alkoxycarbonyl group, and the “halogeno-C₁₋₃ alkoxycarbonyl group”indicates a carbonyl group which is substituted with the aforementionedhalogeno-C₁₋₃ alkoxy group. Examples of the “halogeno-C₁₋₃alkoxycarbonylamino group” include a trifluoromethoxycarbonylaminogroup, a trichloromethoxycarbonylamino group, a2-fluoroethoxycarbonylamino group, a 2,2-difluoroethoxycarbonylaminogroup, and a 2,2,2-trifluoroethoxycarbonylamino group.

As described herein, the “halogeno-C₁₋₃ alkylcarbonylamino group”indicates an amino group which is substituted with one halogeno-C₁₋₃alkylcarbonyl group, and the “halogeno-C₁₋₃ alkylcarbonyl group”indicates a carbonyl group which is substituted with the aforementionedhalogeno-C₁₋₃ alkyl group. Examples of the “halogeno-C₁₋₃alkylcarbonylamino group” include a trifluoromethylcarbonylamino group,a trichloromethylcarbonylamino group, a 2-fluoroethylcarbonylaminogroup, a 2,2-difluoroethylcarbonylamino group, and a2,2,2-trifluoroethylcarbonylamino group.

As described herein, the “heterocycloalkanecarbonyl group” indicates acarbonyl group which is substituted with the aforementionedheterocycloalkyl group, and examples thereof include a4-piperidin-1-carbonyl group, a 4-piperazin-1-carbonyl group, anaziridine-1-carbonyl group, and a morpholine-4-carbonyl group.

As described herein, the “C₁₋₆ alkylpyrazolyl group” indicates apyrazolyl group which is substituted with one C₁₋₆ alkyl group describedabove, and examples of the “C₁₋₆ alkylpyrazolyl group” include a1-methyl-1H-pyrazol-5-yl group, a 1-ethyl-1H-pyrazol-5-yl group, a1-propyl-1H-pyrazol-5-yl group, a 1-methyl-1H-pyrazol-3-yl group, and a1-methyl-1H-pyrazol-4-yl group.

As described herein, the “C₁₋₆ alkylsulfonylpiperazinyl group” indicatesa piperazinyl group which is substituted with one C₁₋₆ alkylsulfonylgroup, and the “C₁₋₆ alkylsulfonyl group” indicates a sulfonyl groupsubstituted with the aforementioned C₁₋₆ alkyl group. Examples of the“C₁₋₆ alkylsulfonylpiperazinyl group” include a4-(methylsulfonyl)piperazin-1-yl group, a4-(ethylsulfonyl)piperazin-1-yl group, a4-(propylsulfonyl)piperazin-1-yl group, a4-(isopropylsulfonyl)piperazin-1-yl group, a4-(methylsulfonyl)piperazin-2-yl group, and a4-(methylsulfonyl)piperazin-3-yl group.

As described herein, the “hydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkyl group”indicates the aforementioned C₁₋₆ alkyl group which is substituted withone hydroxy-C₃₋₇ cycloalkyl group described above, and examples of the“hydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkyl group” include a(1-hydroxycyclopropyl)methyl group, a (1-hydroxycyclobutyl)methyl group,a 2-(1-hydroxycyclopropyl)ethyl group, a(1,2-dihydroxycyclopropyl)methyl group, and a(1,2,3-trihydroxycyclopropyl)methyl group.

As described herein, the “halogeno-C₁₋₃ alkylthiazolyl group” indicatesa thiazolyl group which is substituted with one halogeno-C₁₋₃ alkylgroup described above, and examples thereof include a4-(trifluoromethyl)thiazol-2-yl group, a 5-(trifluoromethyl)thiazol-2-ylgroup, a 4-(trichloromethyl)thiazol-2-yl group, and a4-(2,2,2-trifluoroethyl)thiazol-2-yl group.

As described herein, the “halogeno-C₁₋₃ alkyloxadiazolyl group”indicates an oxadiazolyl group which is substituted with onehalogeno-C₁₋₃ alkyl group described above, and examples thereof includea 5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl group, a5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl group, a5-(2-fluoroethyl)-1,3,4-oxadiazol-2-yl group, and a4-(trifluoromethyl)-1,2,3-oxazol-5-yl group.

As described herein, the “pharmaceutically acceptable salt” can be anyone which is in the form of a pharmaceutically acceptable salt, andexamples thereof include a mineral acid salt such as hydrochloric acidsalt, hydrogen bromide acid salt, sulfuric acid salt, nitric acid salt,and phosphoric acid salt, and an organic acid salt such as acetic acidsalt, propionic acid salt, tartaric acid, salt, fumaric acid salt,maleic acid salt, succinic acid salt, malic acid salt, citric acid salt,methanesulfonic acid salt, p-toluenesulfonic acid salt, andtrifuloroacetic acid salt.

As described herein, a group “may be substituted” with a substituentgroup means a state in which the group is substituted with a substituentgroup or the group is not substituted with a substituent group.

The tetrahydropyridopyrimidine compound of the present invention or asalt thereof is characterized in that it has a5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine skeleton, and a grouprepresented by —NHR (R is as defined below) is present on position 4 andcyanobenzene is present on position 7 of the skeleton, and a cyano groupis present on position 4 and a specific group X is present on position 3of the cyanobenzene (X is as defined below). Thetetrahydropyridopyrimidine compound of the present invention or a saltthereof has an antagonist activity for an androgen receptor (AR) andexhibits an anti-tumor effect. Meanwhile, the compound having, insteadof the 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine skeleton,5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine or5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine skeleton does notexhibit either the AR antagonist activity or anti-tumor effect.Furthermore, the compound having, instead of the cyanobenzene in which acyano group is present on position 4 and substituent group X is presenton position 3, another cyanobenzene does not exhibit the aforementionedeffects.

In the aforementioned Patent Literatures 1 to 3, a compound having5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine skeleton is disclosed.However, in none of the Patent Literatures 1 to 3, a compound having agroup represented by —NHR (R is as defined below) on position 4 andcyanobenzene on position 7 of the5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine is disclosed. Furthermore, theusefulness of the 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compound asan anti-tumor agent is not disclosed at all in Patent Literatures 1 to3, and the effect of the compound against AR is not suggested.

The tetrahydropyridopyrimidine compound of the present invention isrepresented by the following general formula (I).

In the general formula (I), X represents a halogen atom, or ahalogeno-C₁₋₃ alkyl group. Examples of the “halogen atom” represented byX include the aforementioned halogen atom, and it is preferably achlorine atom or a bromine atom. Examples of the “halogeno-C₁₋₃ alkylgroup represented by X include the aforementioned halogeno-C₁₋₃ alkylgroup, and it is preferably a trifluoromethyl group. In the generalformula (I), X is preferably a chlorine atom, a bromine atom, or atrifluoromethyl group, and more preferably a chlorine atom, or atrifluoromethyl group.

In the general formula (I), R represents a C₆₋₁₄ aryl group which issubstituted with R¹ and may be substituted simultaneously with R², or a5- or 6-membered heteroaryl group which is substituted with R¹ and maybe substituted simultaneously with R².

The C₆₋₁₄ aryl group of “C₆₋₁₄ aryl group which is substituted with R¹and may be substituted simultaneously with R²” regarding R is theaforementioned C₆₋₁₄ aryl group, and it is preferably a phenyl group.The number of R¹ substituted on the “C₆₋₁₄ aryl group” is 1, and thenumber of R² is 0 or 1.

The heteroaryl group of “5- or 6-membered heteroaryl group which issubstituted with R¹ and may be substituted simultaneously with R²”regarding R is the aforementioned aryl group. The “5- or 6-memberedheteroaryl group” is preferably a pyridinyl group, a pyrazinyl group, apyrimidinyl group, a pyridazinyl group, a triazinyl group, a thiazolylgroup, a thiadiazolyl group, an oxazolyl group, or an oxadiazolyl group.It is more preferably a pyridinyl group, a pyrimidinyl group, apyridazinyl group, a thiazolyl group, an oxazolyl group, or athiadiazolyl group. It is even more preferably a pyridinyl group, or apyridazinyl group. The number of R¹ substituted on the “5- or 6-memberedheteroaryl group” is 1, and the number of R² is 0 or 1.

In the general formula (I), R is preferably a group selected from thegroup consisting of the following groups.

R is even more preferably a group selected from the group consisting ofthe following groups.

R is even more preferably a group selected from the group consisting ofthe following groups.

Regarding R of the general formula (I), R¹ is a hydrogen atom, a phenylgroup, a hydroxy-C₁₋₆ alkyl group, a hydroxy-C₃₋₇ cycloalkyl group, aC₁₋₆ alkoxy group which may be substituted with Ra, a C₃₋₇,cycloalkylaminosulfonyl group, a 3- to 7-membered monocyclicheterocycloalkylsulfonyl group, a halogeno-C₁₋₃ alkoxycarbonylaminogroup, a halogeno-C₁₋₃ alkylcarbonylamino group, a 3- to 7-memberedmonocyclic heterocycloalkanecarbonyl group substituted with ahydroxy-C₁₋₆ alkyl group, or —(CH₂)_(n)—C(═O)—NHRf.

The “hydroxy-C₁₋₆ alkyl group” represented by R¹ is the aforementionedhydroxy-C₁₋₆ alkyl group, preferably the aforementioned C₁₋₄ alkyl groupsubstituted with 1 to 3 hydroxyl groups (hydroxy-C₁₋₄ alkyl group), andmore preferably an ethyl group substituted with 1 to 3 hydroxyl groups(hydroxy-ethyl group) or an isopropyl group substituted with 1 to 3hydroxyl groups (hydroxy-isopropyl group). The number of the hydroxylgroup is preferably 1. More preferably, the “hydroxy-C₁₋₆ alkyl group”is a 1-hydroxyethyl group, or a 2-hydroxypropan-2-yl group.

The “hydroxy-C₃₋₇ cycloalkyl group” represented by R¹ is theaforementioned hydroxy-C₃₋₇ cycloalkyl group, preferably a cyclic alkylgroup with 3 to 5 carbon atoms substituted with 1 to 3 hydroxyl groups(hydroxy-C₃₋₅ cycloalkyl group), more preferably a cyclopropyl groupsubstituted with 1 to 3 hydroxyl groups (hydroxy-cyclopropyl group) or acyclobutyl group substituted with 1 to 3 hydroxyl groups(hydroxy-cyclobutyl group). The number of the hydroxyl group ispreferably 1. More preferably, the “hydroxy-C₃₋₇ cycloalkyl group” is a1-hydroxycyclopropyl group, or a 1-hydroxycyclobutyl group.

The “C₁₋₆ alkoxy group which may be substituted with Ra” represented byR¹ is the aforementioned C₁₋₆ alkoxy group which is substituted with 0to 3 Ra, and it is preferably the aforementioned C₁₋₄ alkoxy group whichis substituted with 0 to 3 Ra. The number of Ra is preferably 0 or 1.

Ra represents a C₁₋₆ alkylpyrazolyl group, a triazolyl group, atetrazolyl group, or a C₁₋₆ alkylsulfonylpiperazinyl group. The “C₁₋₆alkylpyrazolyl group” represented by Ra is a pyrazolyl group which issubstituted with one C₁₋₆ alkyl group described above, preferably apyrazolyl group which is substituted with one C₁₋₄ alkyl group describedabove (C₁₋₄ alkylpyrazolyl group), more preferably a pyrazolyl groupwhich is substituted with one methyl group (methylpyrazolyl group), andeven more preferably a 1-methyl-1H-pyrazol-5-yl group. The “C₁₋₆alkylsulfonylpiperazinyl group” represented by Ra is a piperazinyl groupwhich is substituted with one sulfonyl group substituted with the C₁₋₆alkyl group described above, preferably a piperazinyl group which issubstituted with one sulfonyl group substituted with the C₁₋₄ alkylgroup described above (C₁₋₄ alkylsulfonylpiperazinyl group), and morepreferably a piperazinyl group which is substituted with one sulfonylgroup substituted with a methyl group (methylsulfonylpiperazinyl group).

The “C₁₋₆ alkoxy group which may be substituted with Ra” is preferably amethoxy group, an isopropoxy group, an ethoxy group substituted with amethylpyrazolyl group, an ethoxy group substituted with a triazolylgroup, a 2-methylpropoxy group substituted with a triazolyl group, a2-methylpropoxy group substituted with a tetrazolyl group, or ann-propoxy group substituted with a methylsulfonylpiperazinyl group, andmore preferably an isopropoxy group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, or n-propoxy group substituted with amethylsulfonylpiperazinyl group.

The “C₃₋₇ cycloalkylaminosulfonyl group” represented by R¹ is theaforementioned C₃₋₇ cycloalkylaminosulfonyl group, and it is preferablya sulfonyl group which is substituted with an amino group substitutedwith one cyclic alkyl group with 3 to 5 carbon atoms (C₃₋₅cycloalkylaminosulfonyl group) and more preferably acyclopropylaminosulfonyl group.

The “3- to 7-membered monocyclic heterocycloalkylsulfonyl group”represented by R¹ is a sulfonyl group substituted with theaforementioned heterocycloalkyl group, and it is preferably a sulfonylgroup substituted with a 7-membered monocyclic heterocycloalkyl groupand more preferably a 1,4-oxazepanylsulfonyl group.

The “halogeno-C₁₋₃ alkoxycarbonylamino group” represented by R¹ is theaforementioned halogeno-C₁₋₃ alkoxycarbonylamino group, and it ispreferably an amino group which is substituted with one carbonyl groupsubstituted with the aforementioned fluoro-C₁₋₃ alkoxy group(fluoro-C₁₋₃ alkoxycarbonylamino group) and more preferably a2,2,2-trifluoroethoxycarbonylamino group.

The “halogeno-C₁₋₃ alkylcarbonylamino group” represented by R¹ is theaforementioned halogeno-C₁₋₃ alkylcarbonylamino group, and it ispreferably an amino group which is substituted with one carbonyl groupsubstituted with the aforementioned fluoro-C₁₋₃ alkyl group (fluoro-C₁₋₃alkylcarbonylamino group) and more preferably a2,2,2-trifluoroethylcarbonylamino group.

The “3- to 7-membered monocyclic heterocycloalkanecarbonyl groupsubstituted with a hydroxy-C₁₋₆ alkyl group” represented by R¹ is acarbonyl group which is substituted with a 3- to 7-membered monocyclicheterocycloalkane substituted with one hydroxy-C₁₋₆ alkyl groupdescribed above, and it is preferably a 6-membered monocyclicheterocycloalkanecarbonyl group substituted with one hydroxy-C₁₋₄ alkylgroup described above, more preferably a piperidinecarbonyl groupsubstituted with one hydroxy-isopropyl group described above, and evenmore preferably a 4-(2-hydroxypropan-2-yl)piperidinecarbonyl group.

In the group represented by “—(CH₂)_(n)—C(═O)—NHRf” regarding R¹, Rf isa halogeno-C₁₋₃ alkyl group, a hydroxy-C₁₋₆ alkyl group, a hydroxy-C₃₋₇cycloalkyl group, a hydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkyl group, or a C₁₋₆alkyl group substituted with Rfa. n is an integer of from 0 to 3,preferably 0 or 1, and more preferably 0.

The “halogeno-C₁₋₃ alkyl group” represented by Rf is the aforementionedhalogeno-C₁₋₃ alkyl group, and it is preferably the aforementionedfluoro-C₁₋₃ alkyl group, more preferably a 2,2,2-trifluoroethyl group,or a 2,2-difluoroethyl group, and even more preferably a2,2,2-trifluoroethyl group.

The “hydroxy-C₁₋₆ alkyl group” represented by Rf is the aforementionedhydroxy-C₁₋₆ alkyl group, and it is preferably a C₁₋₄ alkyl groupsubstituted with 1 to 3 hydroxyl groups (hydroxy-C₁₋₄ alkyl group), morepreferably a 2-methylpropyl group substituted with 1 to 3 hydroxylgroups (hydroxy-2-methylpropyl group), and even more preferably a2-hydroxy-2-methylpropyl group.

The “hydroxy-C₃₋₇ cycloalkyl group” represented by Rf is theaforementioned hydroxy-C₃₋₇ cycloalkyl group, and it is preferably acyclic alkyl group with 5 to 7 carbon atoms substituted with 1 to 3hydroxyl groups (hydroxy-C₃₋₇ cycloalkyl group), more preferably acyclohexyl group substituted with 1 to 3 hydroxyl groups(hydroxy-cyclohexyl group), and even more preferably a4-hydroxycyclohexyl group.

The “hydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkyl group” represented by Rf is theaforementioned hydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkyl group, and preferablythe aforementioned C₁₋₄ alkyl group which is substituted with one cyclicalkyl group having 3 to 5 carbon atoms substituted with 1 to 3 hydroxylgroups (hydroxy-C₃₋₅ cycloalkyl group) (hydroxy-C₃₋₅ cycloalkyl-C₁₋₄alkyl group), more preferably a methyl group which is substituted withone cyclopropyl group substituted with 1 to 3 hydroxyl groups(hydroxy-cyclopropyl group) (hydroxy-cyclopropylmethyl group), and morepreferably a (1-hydroxycyclopropyl)methyl group.

The “C₁₋₆ alkyl group represented by Rfa” represented by Rf is theaforementioned C₁₋₆ alkyl group substituted with 1 to 3 Rfa, andpreferably the aforementioned C₁₋₄ alkyl group which is substituted with1 to 3 Rfa. The number of Rfa is preferably 1.

Rfa is a C₁₋₆ alkylpyrazolyl group, a halogeno-C₁₋₃ alkylthiazolylgroup, an oxadiazolyl group, or a halogeno-C₁₋₃ alkyloxadiazolyl group.The “C₁₋₆ alkylpyrazolyl group” represented by Rfa is the aforementionedC₁₋₆ alkylpyrazolyl group, and it is preferably a C₁₋₄ alkylpyrazolylgroup, more preferably methylpyrazolyl group, and even more preferably a1-methyl-1H-pyrazol-5-yl group. The “halogeno-C₁₋₃ alkylthiazolyl group”represented by Rfa is the aforementioned halogeno-C₁₋₃ alkylthiazolylgroup, and it is preferably a thiazolyl group substituted with onefluoro-C₁₋₃ alkyl group described above (fluoro-C₁₋₃ alkylthiazolylgroup), more preferably a thiazolyl group substituted with onetrifluoromethyl group (trifluoromethylthiazolyl group), and even morepreferably a 4-(trifluoromethyl)thiazol-2-yl group. The “halogeno-C₁₋₃alkyloxazolyl group” represented by Rfa is the aforementionedhalogeno-C₁₋₃ alkyloxazolyl group, and it is preferably an oxadiazolylgroup substituted with one fluoro-C₁₋₃ alkyl group described above(fluoro-C₁₋₃ alkyloxazolyl group), more preferably an oxadiazolyl groupsubstituted with one trifluoromethyl group (trifluoromethyloxazolylgroup), and even more preferably a5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl group.

The “C₁₋₆ alkyl group substituted with Rfa” is preferably theaforementioned C₁₋₄ alkyl group which is substituted with any one of oneC₁₋₄ alkylpyrazolyl group described above, one fluoro-C₁₋₃alkylthiazolyl group described above, one oxadiazolyl group, and onefluoro-C₁₋₃ alkyloxadiazolyl group described above. More preferably, itis a methyl group substituted with one trifluoromethylthiazolyl groupdescribed above, an ethyl group substituted with one methylthiazolylgroup described above, an ethyl group substituted with one oxadiazolylgroup described above, or an ethyl group substituted with onetrifluoromethyloxadiazolyl group described above. Even more preferably,it is a 2-(1-methyl-1H-pyrazol-5-yl)ethyl group, a(4-(trifluoromethyl)thiazol-2-yl)methyl group, a1-(1,3,4-oxadiazol-2-yl)ethyl group, or a1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethyl group. Even morepreferably, it is a (4-(trifluoromethyl)thiazol-2-yl)methyl group.

Regarding the general formula (I), it is preferable that:

R¹ is a hydrogen atom, a phenyl group, a hydroxy-C₁₋₄ alkyl group, ahydroxy-C₃₋₅ cycloalkyl group, a C₁₋₄ alkoxy group which may besubstituted with Ra, a C₃₋₅ cycloalkylaminosulfonyl group, a 7-memberedmonocyclic heterocycloalkylsulfonyl group, a fluoro-C₁₋₃alkoxycarbonylamino group, a fluoro-C₁₋₃ alkylcarbonylamino group, a6-membered monocyclic heterocycloalkanecarbonyl group substituted with ahydroxy-C₁₋₄ alkyl group, or —(CH₂)_(n)—C(═O)—NHRf;Ra is a C₁₋₄ alkylpyrazolyl group, a triazolyl group, a tetrazolylgroup, or a C₁₋₄ alkylsulfonylpiperazinyl group;Rf is a halogeno-C₁₋₃ alkyl group, a hydroxy-C₁₋₄ alkyl group, ahydroxy-C₅₋₇ cycloalkyl group, a hydroxy-C₃₋₅ cycloalkyl-C₁₋₄ alkylgroup, or a C₁₋₄ alkyl group substituted with Rfa;Rfa is a C₁₋₄ alkylpyrazolyl group, a fluoro-C₁₋₃ alkylthiazolyl group,an oxadiazolyl group, or a fluoro-C₁₋₃ alkyloxadiazolyl group; andn is 0 or 1.

Regarding the general formula (I), it is more preferable that:

R¹ is a hydrogen atom, a phenyl group, a hydroxy-ethyl group, ahydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, a methoxy group, an isopropoxy group, anethoxy group substituted with a methylpyrazolyl group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, an n-propoxy group substituted with amethylsulfonylpiperazinyl group, a cyclopropylaminosulfonyl group, a1,4-oxazepanylsulfonyl group, a 2,2,2-trifluoroethoxycarbonylaminogroup, a 2,2,2-trifluoroethylcarbonylamino group, a piperidinecarbonylgroup substituted with a hydroxy-isopropyl group, or—(CH₂)_(n)—C(═O)—NHRf;Rf is a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a hydroxycyclohexyl group, ahydroxycyclopropylmethyl group, a methyl group substituted with atrifluoromethylthiazolyl group, an ethyl group substituted with amethylthiazolyl group, an ethyl group substituted with an oxadiazolylgroup, or an ethyl group substituted with trifluoromethyloxazolyl group;andn is 0 or 1.

In the general formula (I), R² represents a hydrogen atom, a halogenatom, or a halogeno-C₁₋₃ alkyl group. Examples of the “halogen atom”include the aforementioned halogen atom, and it is preferably a fluorineatom or a chlorine atom. Examples of the “halogeno-C₁₋₃ alkyl group”include the aforementioned halogeno-C₁₋₃ alkyl group, and it ispreferably a trifluoromethyl group. R² is preferably a hydrogen atom, afluorine atom, a chlorine atom, or a trifluoromethyl group. Morepreferably, it is a hydrogen atom or a fluorine atom.

In the general formula (I), examples of the C₆₋₁₄ aryl group which issubstituted with R¹ and may be substituted simultaneously with R² andthe 5- or 6-membered heteroaryl group which is substituted with R¹ andmay be substituted simultaneously with R² include the followings:

(in the formula, R¹ is a hydrogen atom);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a C₁₋₆ alkyl group substituted with Rfa,Rfa is a C₁₋₆ alkylpyrazolyl group, or an oxadiazolyl group, andn is 0);

(in the formula,R¹ is a phenyl group, a hydroxy-C₁₋₄ alkyl group, a hydroxy-C₃₋₇cycloalkyl group, or a C₁₋₆ alkoxy group which may be substituted withRa,R² is a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group,andRa is a C₁₋₆ alkylpyrazolyl group, or a C₁₋₆ alkylsulfonylpiperazinylgroup);

(in the formula,R¹ is the aforementioned hydroxy-C₁ alkyl group, hydroxy-C₃₋₇ cycloalkylgroup, C₁₋₆ alkoxy group which may be substituted with Ra, C₃₋₇cycloalkylaminosulfonyl group, halogeno-C₁₋₃ alkoxycarbonylamino group,halogeno-C₁₋₃ alkylcarbonylamino group, or —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom or a halogen atom,Ra is a triazolyl group, or a tetrazolyl group,Rf is a halogeno-C₁₋₃ alkyl group or a C₁₋₆ alkyl group substituted withRfa,Rfa is a halogeno-C₁₋₃ alkylthiadiazolyl group, an oxadiazolyl group, ora halogeno-C₁₋₃ alkyloxadiazolyl group, and,n is 0 or 1);

(in the formula,R¹ is the aforementioned hydroxy-C₁₋₆ alkyl group, 3- to 7-memberedmonocyclic heterocycloalkylsulfonyl group, or —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group,Rf is a halogeno-C₁₋₃ alkyl group, or a C₁₋₆ alkyl group substitutedwith Rfa,Rfa is an oxadiazolyl group, and,n is 0);

(in the formula,R¹ is the aforementioned hydroxy-C₁₋₆ alkyl group, or—(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group,Rf is a halogeno-C₁₋₃ alkyl group, a hydroxy-C₁₋₆ alkyl group, ahydroxy-C₃₋₇ cycloalkyl group, or a hydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkylgroup, and,n is 0);

(in the formula,R¹ is the aforementioned —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group,Rf is a hydroxy-C₁₋₆ alkyl group, and,n is 0);

(in the formula,R¹ is the aforementioned —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group,Rf is a hydroxy-C₁₋₆ alkyl group, and,n is 0);

(in the formula,R¹ is the aforementioned —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group,Rf is a halogeno-C₁₋₃ alkyl group, and,n is 0);

(in the formula,R¹ is a 3- to 7-membered monocyclic cycloheteroalkanecarbonyl groupwhich is substituted with the aforementioned hydroxy-C₁₋₆ alkyl group,R² is a hydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group);and,

(in the formula, R¹ a 3- to 7-membered monocycliccycloheteroalkanecarbonyl group which is substituted with theaforementioned hydroxy-C₁₋₆ alkyl group).

Regarding the general formula (I), more preferred combination of R, R¹,and R² is described below:

(in the formula, R¹ is a hydrogen atom);

(in the formula,R¹ represents —(CH₂)_(n)—C(═O)—NHRf,Rf represents a methyl group substituted with Rfa or an ethyl groupsubstituted with Rfa,Rfa is a methylpyrazolyl group or an oxadiazolyl group, and,n is 0);

(in the formula,R¹ is phenyl group, a hydroxy-ethyl group, a hydroxy-isopropyl group, amethoxy group, an isopropoxy group, an ethoxy group substituted with amethylpyrazolyl group, or an n-propoxy group substituted with amethylsulfonylpiperazinyl group);

(in the formula,R¹ is a hydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, an isopropoxy group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, a cyclopropylaminosulfonyl group, a2,2,2-trifluoroethoxycarbonylamino group, a2,2,2-trifluoroethylcarbonylamino group, or —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a fluorine atom, or a chlorine atom,Rf represents a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, amethyl group substituted with Rfa, or an ethyl group substituted withRfa;Rfa is a trifluoromethylthiazolyl group, an oxadiazolyl group, or atrifluoromethyloxadiazolyl group, and,n is 0 or 1);

(in the formula,R¹ is a hydroxy-isopropyl group, a 1,4-oxazepanylsulfonyl group, or—(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom or a trifluoromethyl group,Rf is a 2,2,2-trifluoroethyl group, or an ethyl group substituted withRfa,Rfa is an oxadiazolyl group, and,n is 0);

(in the formula,R¹ is a hydroxy-isopropyl group or —(CH₂)_(n)—C(═O)—NHRf,Rf is a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a hydroxycyclohexyl group, or ahydroxycyclopropylmethyl group, andn is 0);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a hydroxy-2-methylpropyl group, andn is 0);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a hydroxy-2-methylpropyl group, andn is 0);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a 2,2,2-trifluoroethyl group, andn is 0);

(in the formula,R¹ is a piperidinecarbonyl group substituted with a hydroxy-isopropylgroup); or

(in the formula,R¹ is a piperidinecarbonyl group substituted with a hydroxy-isopropylgroup).

Regarding the general formula (I), even more preferred combination of R,R¹, and R² is described below:

(in the formula, R¹ is a hydrogen atom);

(in the formula, R¹ is an isopropoxy group, or an n-propoxy groupsubstituted with a methylsulfonylpiperazinyl group);

(in the formula,R¹ is the aforementioned hydroxy-isopropyl group, a 2-methylpropoxygroup substituted with a tetrazolyl group, or —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom or a fluorine atom,Rf is a 2,2,2-trifluoroethyl group, a methyl group substituted with atrifluoromethylthiazolyl group, an ethyl group substituted with anoxadiazolyl group, or an ethyl group substituted with atrifluoromethyloxadiazolyl group, andn is 0);

R¹

(in the formula, R¹ is an isopropoxy group, or a 2-methylpropoxy groupsubstituted with a tetrazolyl group);

(in the formula, R¹ is a 1,4-oxazepanylsulfonyl group);

(in the formula,R¹ is the aforementioned hydroxy-isopropyl group, or—(CH₂)_(n)—C(═O)—NHRf,Rf is the aforementioned hydroxy-2-methylpropyl group, andn is 0);

(in the formula,R¹ is —(CH₂)_(n)—C(═O)—NHRf,Rf is a hydroxy-2-methylpropyl group, andn is 0); or

(in the formula, R¹ is a piperidinecarbonyl group substituted with ahydroxy-isopropyl group).

According to a preferred embodiment, in the general formula (I),

X is a chlorine atom, a bromine atom, or a trifluoromethyl group;R is a group selected from the group consisting of the following groups;

R¹ is a hydrogen atom, a phenyl group, a hydroxy-C₁₋₄ alkyl group, ahydroxy-C₃₋₅ cycloalkyl group, a C₁₋₄ alkoxy group which may besubstituted with Ra, a C₃₋₅ cycloalkylaminosulfonyl group, a 7-memberedmonocyclic heterocycloalkylsulfonyl group, a fluoro-C₁₋₅alkoxycarbonylamino group, a fluoro-C₁₋₃ alkylcarbonylamino group, a6-membered monocyclic heterocycloalkanecarbonyl group substituted with ahydroxy-C₁₋₄ alkyl group, or —(CH₂)_(n)—C(═O)—NHRf;R² is a hydrogen atom, a fluorine atom, a chlorine atom, or atrifluoromethyl group;Ra is a C₁₋₄ alkylpyrazolyl group, a triazolyl group, a tetrazolylgroup, or a C₁₋₄ alkylsulfonylpiperazinyl group;Rf is a fluoro-C₁₋₃ alkyl group, a hydroxy-C₁₋₄ alkyl group, ahydroxy-C₃₋₅ cycloalkyl group, a hydroxy-C₃₋₅ cycloalkyl-C₁₋₄ alkylgroup, or a C₁₋₄ alkyl group substituted with Rfa;Rfa is a C₁₋₄ alkylpyrazolyl group, a fluoro-C₁₋₃ alkylthiazolyl group,an oxadiazolyl group, or a fluoro-C₁₋₃ alkyloxadiazolyl group; andn is 0 or 1.

According to a more preferred embodiment, in the general formula (I),

X is a chlorine atom, a bromine atom, or a trifluoromethyl group;R is a group selected from the group consisting of the following groups;

R¹ is a hydrogen atom, a phenyl group, a hydroxy-ethyl group, ahydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, a methoxy group, an isopropoxy group, anethoxy group substituted with a methylpyrazolyl group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, an n-propoxy group substituted with amethylsulfonylpiperazinyl group, a cyclopropylaminosulfonyl group, a1,4-oxazepanylsulfonyl group, a 2,2,2-trifluoroethoxycarbonylaminogroup, a 2,2,2-trifluoroethylcarbonylamino group, a piperidinecarbonylgroup substituted with a hydroxy-isopropyl group, or—(CH₂)_(n)—C(═O)—NHRf;R² is a hydrogen atom, a fluorine atom, a chlorine atom, or atrifluoromethyl group;Rf is a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a hydroxycyclohexyl group, ahydroxycyclopropylmethyl group, a methyl group substituted with atrifluoromethylthiazolyl group, an ethyl group substituted with amethylthiazolyl group, an ethyl group substituted with an oxadiazolylgroup, or an ethyl group substituted with a trifluoromethyl group; andn is 0 or 1.

According to an even more preferred embodiment, in the general formula(I),

X is a chlorine atom or a trifluoromethyl group;R is a group selected from the group consisting of the following groups;

R¹ is a hydrogen atom, a hydroxy-isopropyl group, an isopropoxy group, a2-methylpropoxy group substituted with a tetrazolyl group, an n-propoxygroup substituted with a methylsulfonylpiperazinyl group, a1,4-oxazepanylsulfonyl group, a piperidinecarbonyl group substitutedwith a hydroxy-isopropyl group, or —(CH₂)_(n)—C(═O)—NHRf;R² is a hydrogen atom or a fluorine atom;Rf is a 2,2,2-trifluoroethyl group, a hydroxy-2-methylpropyl group, amethyl group substituted with a trifluoromethylthiazolyl group, an ethylgroup substituted with an oxadiazolyl group, or an ethyl groupsubstituted with a trifluoromethyloxadiazolyl group; andn is 0.

Specific examples of the tetrahydropyridopyrimidine compound that arepreferred in the present invention include the compounds described inthe following (1) to (19).

-   (1)    4-(4-((1,2,4-thiadiazol-5-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile    (Example 1)-   (2)    4-(4-((4-isopropoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile    (Example 2)-   (3)    4-(4-((6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)-2-(trifluoromethyl)benzonitrile (Example 5)-   (4)    2-chloro-4-(4-((6-(2-hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)benzonitrile (Example 6)-   (5)    4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile    (Example 7)-   (6)    2-chloro-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)benzonitrile (Example 9)-   (7)    4-(4-((6-(2-hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)-2-(trifluoromethyl)benzonitrile (Example 10)-   (8)    6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8,-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide    (Example 11)-   (9)    4-(4-((6-isopropoxypyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile    (Example 13)-   (10)    4-(4-((6-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile    (Example 16)-   (11)    4-(4-((5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile    (Example 17)-   (12) 4-(4-((4-(3-(4-(methylsulfonyl)    piperazin-1-yl)propoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile    (Example 18)-   (13) 4-(4-((5-((1,4-oxazepan-4-yl) sulfonyl)    thiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7    (8H)-yl)-2-(trifluoromethyl)benzonitrile (Example 20)-   (14)    6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyridazine-3-carboxamide    (Example 32)-   (15)    2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyrimidine-5-carboxamide    (Example 34)-   (16)    6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl)nicotinamide    (Example 36)-   (17)    (R)—N-(1-(1,3,4-oxadiazol-2-yl)ethyl)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinamide    (Example 38)-   (18)    (R)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethyl)nicotinamide    (Example 40)-   (19)    4-(4-((5-(4-(2-hydroxypropan-2-yl)piperidin-1-carbonyl)oxazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Example 42

The tetrahydropyridopyrimidine compound of the present invention or asalt thereof can be produced by various methods. The compoundrepresented by the general formula (I) can be produced according to agenerally known method. The compound represented by the general formula(I) can be produced by the following Reaction schemes 1 to 6, forexample. In Reaction schemes 1 to 6, X, R, R¹, R², Rf, and Ra are asdefined above.

The present reaction scheme is a reaction scheme for synthesizing thegeneral formula (I) from the formula (II).

(Step 1)

This step is a reaction for deprotecting the protecting group P of thecompound of the formula (II) shown in Reaction scheme 1 above. As forthe method for deprotection, it can be performed by a generally knownmethod, for example, the method described in Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons (1981) or a methodsimilar to it. Examples of the protecting group include a Boc group, abenzyloxycarbonyl group, and a benzyl group. When a benzyl group is usedas a protecting group, examples of the catalyst for hydrogenolysisinclude palladium hydroxide, palladium/carbon, platinum, Raney nickel,platinum oxide, and rhodium-aluminum oxide. Preferably, it ispalladium/carbon. The amount used of the reagent is, relative to 1 eqv.of the compound of the formula (II), 0.001 to 10 eqv., and preferably0.05 to 2 eqv. Temperature for deprotecting reaction is 0 to 100° C.,and preferably 40 to 80° C. The compound of the formula (III) obtainedby this step can be separated and purified by a known means forseparation and purification, for example, concentration, concentrationunder reduced pressure, crystallization, re-precipitation, andchromatography, or it can be subjected to the next step without anyseparation and purification.

(Step 2)

This step is a step for producing the compound represented by theformula (V) according to a nucleophilic substitution reaction betweenthe amine represented by the formula (III) and the aromatic ringsubstituted with the leaving group L¹ represented by the formula (IV).Examples of the leaving group L¹ include, in addition to a halogen atomsuch as fluorine and chlorine, a methanesulfonyloxy group, ap-toluenesulfonyloxy group, and a trifluoromethylsulfonyloxy group. Thesolvent used for this step is not particularly limited as long as itdoes not cause any problem on the reaction. Examples of the solventinclude toluene, acetonitrile, benzene, dioxane, THF, DMSO, DMF,pyridine, and a mixed solvent thereof. It is preferably DMSO. Theequivalent of the aromatic ring represented by the formula (IV), whichis used for this reaction, is 0.1 to excess mol and preferably 0.5 to 3mol relative to 1 mol of the amine represented by the formula (III). Forthe reaction, a base may be either used or not used. When a base isused, examples of the base include pyridine, DBU, potassium carbonate,cesium carbonate, and a tertiary amine. Preferably, it is triethylamine.The temperature for the nucleophilic substitution reaction is 0 to 200°C., and preferably 0 to 50° C. The compound of the formula (V) obtainedby this step can be separated and purified by a known means forseparation and purification, for example, concentration, concentrationunder reduced pressure, crystallization, re-precipitation, andchromatography, or it can be subjected to the next step without anyseparation and purification.

(Step 3)

This step is a step for converting the free hydroxyl group of thecompound of the formula (V) to a leaving group L². Examples of theleaving group L² include the same groups as L¹, and it is preferably ahalogen atom. The conversion reaction is carried out without a solventor in the presence of a solvent. Examples of the solvent which can beused for this step is not particularly limited as long as it does notcause any problem on the reaction. Examples of the solvent include DMF,NMP, DMA, toluene, dichloroethane, and acetonitrile. Examples of thebase used for the reaction include triethylamine, diisopropylethylamine,N,N-dimethylaniline, and sodium hydrogen carbonate. The amount of thehalogenating agent used for the reaction (e.g., phosphorus oxychloride,phosphorus pentachloride, and phosphorus tribromide) is, relative to 1mol of the compound of the formula (V), 0.5 to 20 mol, and preferably 5to 15 mol. The time of the conversion reaction is 0.1 to 48 hours, andpreferably 0.5 to 24 hours. The reaction temperature is 0 to 200° C.,and preferably 50 to 120° C. The compound of the formula (VI) obtainedby this step can be separated and purified by a known means forseparation and purification, for example, concentration, concentrationunder reduced pressure, crystallization, re-precipitation, andchromatography, or it can be subjected to the next step without anyseparation and purification.

(Step 4)

This step is a step for obtaining the compound of the general formula(I) by linking the compound of the formula (VI) to the compound of theformula (VII). The reaction of this step is performed by using a metalcatalyst and a phosphine ligand in a suitable solvent, in the presenceof various bases. As the metal catalyst, a metal complex having variousligands can be used, and examples thereof includetetrakistriphenylphosphine palladium (0),chlorobis(triphenylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and palladium acetate (II).Examples of the phosphine ligand include dppf, Xantphos, and XPhos.Examples of the base used for the reaction of this step includepotassium carbonate, cesium carbonate, and sodium tert-butoxide. Thesolvent which can be used for this step is not particularly limited aslong as it does not cause any problem on the reaction. Examples of thesolvent include dioxane, ethyl acetate, and toluene. The amount of themetal catalyst used for the reaction is, relative to 1 mol of thecompound of the formula (VI), 0.005 to 10 mol, and preferably 0.01 to 1mol. The time of the reaction is 0.1 to 48 hours, and preferably 0.5 to24 hours. The reaction temperature is 0 to 200° C., and preferably 50 to120° C. The compound of the formula (I) obtained by this step can beseparated and purified by a known means for separation and purification,for example, concentration, concentration under reduced pressure,crystallization, re-precipitation, and chromatography.

According to another method for this step, the compound represented bythe general formula (I) can be obtained by using only a base withoutusing the metal catalyst and phosphine ligand. Examples of the baseinclude potassium carbonate. The amount of the base is, relative to 1mol of the compound of the formula (VI), 0.005 to 10 mol, and preferably1.0 to 5.0 mol. The solvent used for the reaction of this step is notparticularly limited as long as it does not cause any problem on thereaction. Examples of the solvent include acetonitrile and dioxane. Thetime of the reaction is 0.1 to 48 hours, and preferably 0.5 to 24 hours.The reaction temperature is 0 to 200° C., and preferably 50 to 120° C.The compound of the general formula (I) obtained by this step can beseparated and purified by a known means for separation and purification,for example, concentration, concentration under reduced pressure,crystallization, re-precipitation, and chromatography.

As another method for this step, the linking between the compound of theformula (VI) and the compound of the formula (VII) can be performedunder irradiation of microwave. In that case, the aforementioned basecan be used as a base of this step; however, it is also possible to useno base. The solvent used for the reaction of this step is notparticularly limited as long as it does not cause any problem on thereaction. Examples of the solvent include acetonitrile. The time of thereaction is 0.01 to 10 hours, and preferably 0.1 to 1 hour. The reactiontemperature is 0 to 200° C., and preferably 100 to 200° C. The compoundof the general formula (I) obtained by this step can be separated andpurified by a known means for separation and purification, for example,concentration, concentration under reduced pressure, crystallization,re-precipitation, and chromatography.

As another method for this step, the linking between the compound of theformula (VI) and the compound of the formula (VII) can be performed byusing an acid instead of using the metal catalyst and phosphine ligand.The equivalent of the compound of the formula (VII) is, relative to 1mol of the compound of the formula (VI), 0.1 to excess mol, andpreferably 1 to 10 mol. Examples of the acid which is used includeparatoluenesulfonic acid, camphorsulfonic acid, and hydrochloric acid.The amount of the acid is, relative to 1 mol of the compound of theformula (VI), 0.005 to excess mol, and preferably 0.1 to 10 mol. Thesolvent used for the reaction of this step is not particularly limitedas long as it does not cause any problem on the reaction. Examples ofthe solvent include tert-butanol, 2-propanol, THF, and dioxane. The timeof the reaction is 0.1 to 48 hours, and preferably 0.1 to 24 hours. Thereaction temperature is 0 to 200° C., and preferably 50 to 180° C. Thecompound of the general formula (I) obtained by this step can beseparated and purified by a known means for separation and purification,for example, concentration, concentration under reduced pressure,crystallization, re-precipitation, and chromatography.

The present reaction scheme can be applied when R substituted on R ofthe general formula (I) is —(CH₂)_(n)—C(═O)—NHRf, or a 3- to 7-memberedmonocyclic nitrogen-containing heterocycloalkyl group substituted withhydroxy-C₁₋₆ alkyl group.

(Step 5)

This step is a step for obtaining the compound represented by theformula (VIII) through hydrolysis of an ester group of the compoundrepresented by the formula (I′) by a commonly known method. In theformula (I′), Ar is a C₆₋₁₄ aryl group, or a 5- or 6-membered heteroarylgroup, n is an integer of 0 to 3, and R² is as defined above. Thecompound of the formula (I′) can be produced according to the process ofthe aforementioned Reaction scheme 1. As for the method for deprotectingthe protecting group P′, it can be performed by a generally knownmethod, for example, the method described in Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons (1981) or a methodsimilar to it. Examples of the protecting group P′ include a methylgroup and an ethyl group. In that case, deprotection under basiccondition is preferable, and examples of the base include an inorganicbase such as sodium hydroxide and potassium hydroxide. The amount usedof the base is, relative to 1 mol of the compound of the formula (I′), 1to 100 mol. The solvent used for the reaction of this step is notparticularly limited as long as it does not cause any problem on thereaction. Examples of the solvent include water, methanol, ethanol,diethyl ether, and THF. The time of the reaction is 0.1 to 100 hours,and preferably 0.5 to 24 hours. Temperature for the reaction is 0 to120° C., and preferably 0 to 90° C. The compound of the formula (VIII)obtained by this step can be separated and purified by a known means forseparation and purification, for example, concentration, drying underreduced pressure, crystallization, re-precipitation, solvent extraction,and chromatography, or it can be subjected to the next step without anyseparation and purification.

(Step 6)

This step is a step for synthesizing the compound represented by thegeneral formula (X) through condensation between the compoundrepresented by the formula (VIII) and the amine represented by theformula (IX). The group represented by —N(Rf¹) (Rf²) in the formula (IX)is —NHRf or a 3- to 7-membered monocyclic nitrogen-containingheterocycloalkyl group substituted with hydroxy-C₁₋₆ alkyl group. Thesolvent used for the reaction of this step is not particularly limitedas long as it does not cause any problem on the reaction. Examples ofthe solvent include DMF, toluene, dichloromethane, acetonitrile, THF,and DMSO. It is preferably DMF or methanol. Examples of the condensingagent include DCC, WSC/1-hydroxybenzotriazole (hereinbelow, HOBt),DMT-MM, and HATU. It is preferably WSC/HOBt, DMT-MM, or HATU. The numberof the equivalents of the condensing agent is, relative to 1 eqv. of thecompound of the formula (VIII), 0.2 to 5.0 eqv., and preferably 1.0 to1.5 eqv. Furthermore, a base such as DIPEA can be used, if necessary.Temperature for the reaction is 0 to 100° C., and preferably 10 to 40°C. Time for the reaction is 0.1 to 24 hours, and preferably 0.5 to 16hours. The compound of the formula (X) obtained by this step can beseparated and purified by a known means for separation and purification,for example, concentration, drying under reduced pressure,crystallization, re-precipitation, solvent extraction, andchromatography.

The present reaction scheme can be applied when R¹ substituted on R ofthe general formula (I) is a halogeno-C₁₋₃ alkylcarbonylamino group.

(Step 7)

This step is a reaction for obtaining the compound represented by theformula (XI) through a commonly known contact reduction of the nitrogroup of the compound represented by the formula (I″). The compound ofthe formula (I″) can be produced according to the process of theaforementioned Reaction scheme 1. The solvent used for the reaction ofthis step is not particularly limited as long as it does not cause anyproblem on the reaction. Examples of the solvent include methanol,ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, dimethoxyethane,diethylene glycol dimethyl ether, diisopropyl ether, diethyl ether, THF,dioxane, ethyl acetate, and butyl acetate. It is preferably methanol orethanol. Examples of the catalyst used for this step includepalladium/carbon, palladium hydroxide/carbon, platinum, Raney nickel,platinum oxide, and rhodium-aluminum oxide. Preferably, it ispalladium/carbon. The number of the equivalents of the catalyst is,relative to 1 eqv. of the compound of the formula (I″), 0.001 to 10eqv., and preferably 0.01 to 5.0 eqv. Temperature for the reducingreaction is 0 to 100° C., and preferably 20 to 60° C. Time for thereaction is 0.1 to 72 hours, and preferably 6 to 72 hours. The compoundof the formula (XI) obtained by this step can be separated and purifiedby a known means for separation and purification, for example,concentration, concentration under reduced pressure, crystallization,re-precipitation, and chromatography, or it can be subjected to the nextstep without any separation and purification.

(Step 8)

This step is an amidation between the compound represented by thegeneral formula (XI) and the carboxylic acid represented by the formula(XII). Ree² is a halogeno-C₁₋₃ alkyl group. The solvent used for thereaction of this step is not particularly limited as long as it does notcause any problem on the reaction. Examples of the solvent include DMF,toluene, dichloromethane, acetonitrile, THF, and DMSO. It is preferablyDMF or methanol. Examples of the condensing agent which is used for thisstep include DCC, WSC/HOBt, DMT-MM, and HATU. It is preferably WSC/HOBt,DMT-MM, or HATU. The number of the equivalents of the condensing agentis, relative to 1 eqv. of the compound of the formula (XI), 0.2 to 5.0eqv., and preferably 1.0 to 1.5 eqv. Furthermore, a base such as DIPEAcan be used, if necessary. Temperature for the amidation reaction is 0to 100° C., and preferably 10 to 40° C. Time for the reaction is 0.1 to24 hours, and preferably 0.5 to 16 hours. The compound of the formula(XIII) obtained by this step can be separated and purified by a knownmeans for separation and purification, for example, concentration,concentration under reduced pressure, crystallization, re-precipitation,and chromatography.

The present reaction scheme can be applied when R¹ substituted on R ofthe general formula (I) is a halogeno-C₁₋₃ alkoxycarbonylamino group.Ree² has the same meaning as the aforementioned Ree².

(Step 9)

This step is a step for obtaining the compound represented by theformula (XV) from the compound represented by the formula (VIII′). Thisstep is a Cutius transition reaction between the compound represented bythe formula (VIII′) and an alcohol represented by the formula (XIV).Examples of the base which is used for this step include triethylamineand N,N-diisopropylamine. The amount used of the base is, relative to 1eqv. of the compound of the formula (VIII′), 1 to 10 eqv., for example.Examples of an azidation reagent include sodium azide and DPPA. Theamount used of the azidation reagent is, relative to 1 eqv. of thecompound of the formula (VIII′), 1 to 5 eqv. The amount used of thealcohol represented by the formula (XIV) is, relative to 1 eqv. of thecompound of the formula (VIII′), generally 1 to 10 eqv. and preferably 2to 5 eqv. Examples of the solvent used for this step includedichloromethane, chloroform, THF, toluene, and dioxane. Temperature forthe reaction is 0° C. to 200° C. Time for the reaction is 0 to 24 hours.If necessary, the reaction can be performed under irradiation ofmicrowave. The compound of the formula (XV) obtained by this step can beseparated and purified by a known means for separation and purification,for example, concentration, concentration under reduced pressure,crystallization, re-precipitation, and chromatography.

The present reaction scheme can be applied when R¹ substituted on R ofthe general formula (I) is a C₁₋₆ alkoxy group which may be substitutedwith Ra. —OR³ indicates a C₁₋₆ alkoxy group which may be substitutedwith Ra.

(Step 10)

This step is a reaction for deprotecting the protecting group P″ of theformula (I′″). The compound of the formula (I′″) can be producedaccording to the process of the aforementioned Reaction scheme 1. As forthe method for deprotection, it can be performed by a generally knownmethod, for example, the method described in Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons (1981) or a methodsimilar to it. Examples of the protecting group P″ include abenzyloxymethyl group (BOM), methoxyethoxymethyl group (MEM), tert-butylgroup, and a benzyl group. When a benzyl group is used as a protectinggroup P″, examples of the catalyst for hydrogenolysis include palladiumhydroxide, palladium/carbon, platinum, Raney nickel, platinum oxide, andrhodium-aluminum oxide. Preferably, it is palladium/carbon. The solventused for the reaction of this step is not particularly limited as longas it does not cause any problem on the reaction. Examples of thesolvent include methanol, ethanol, 1-propanol, 2-propanol, tert-butylalcohol, dimethoxyethane, diethylene glycol dimethyl ether, diisopropylether, diethyl ether, THF, dioxane, ethyl acetate, and butyl acetate. Itis preferably methanol or ethanol. The amount used of the catalyst is,relative to 1 eqv. of the compound of the formula (I′″), 0.001 to 10eqv., and preferably 0.05 to 2 eqv. Temperature for the reaction is 0 to100° C., and preferably 40 to 80° C. The compound of the formula (XVI)obtained by this step can be separated and purified by a known means forseparation and purification, for example, concentration, concentrationunder reduced pressure, re-precipitation, crystallization, andchromatography, or it can be subjected to the next step without anyseparation and purification.

(Step 11)

This step relates to a method for producing the compound of the formula(XVIII) from the compound of the formula (XVI). This step can beperformed by a known method, that is, a so-called Mitsunobu reaction(Synthesis, 1981, 1-28). The amount of the compound represented by theformula (XVII) which is used for this step is, relative to 1 eqv. of thecompound of the formula (XVI), 0.5 to 5 eqv. and preferably 1 to 3 eqv.Examples of the azo compound used for this reaction include diethylazodicarboxylate, diisopropyl azodicarboxylate, and1,1′-azobis(N,N-dimethylformamide). The amount of the azo compound whichis used is, relative to 1 eqv. of the compound of the formula (XVI), 1to 5 eqv., and preferably 1.1 to 3 eqv. Examples of the phosphinecompound which is used include triphenylphosphine and tributylphosphine.The amount of the phosphine compound which is used is, relative to 1eqv. of the compound of the formula (XVI), 1 to 5 eqv., and preferably1.1 to 3 eqv. The solvent which can be used for this step is notparticularly limited as long as it does not cause any problem on thereaction. Examples of the solvent include THF, dioxane, diethyl ether,chloroform, dichloromethane, toluene, DMF, and dimethyl sulfoxide. Thosesolvents can be used as a mixture in which they are mixed at anappropriate ratio. The reaction temperature is between room temperatureand reflux temperature. The time of the reaction is 1 to 4 hours. Thecompound of the formula (XVIII) obtained by this step can be separatedand purified by a known means for separation and purification, forexample, concentration, concentration under reduced pressure,crystallization, re-precipitation, and chromatography.

Furthermore, the reaction of this step can be performed by using areagent such as (cyanomethylene)trimethylphosphrane and(cyanomethylene)tributylphosphrane (Tsunoda Reagent). The amount of thereagent which is used is, relative to 1 eqv. of the compound of theformula (XVI), 1 to 5 eqv., and preferably 1.1 to 3 eqv. Examples of thesolvent which is used for the reaction include the aforementionedsolvent for this step. The reaction temperature is between roomtemperature and reflux temperature. The reaction time is 1 to 48 hours.The compound of the formula (XVIII) obtained by this step can beseparated and purified by a known means for separation and purification,for example, concentration, concentration under reduced pressure,re-precipitation, solvent extraction, crystallization, andchromatography.

The present reaction scheme can be applied when R¹ substituted on R ofthe general formula (I) is a C₁₋₆ alkoxy group which may be substitutedwith Ra in which Ra is a C₁₋₆ alkylsulfonylpiperazinyl group. Herein, ann-propyl group is exemplified as a C₁₋₆ alkoxy group. R¹ is a C₁₋₆ alkylgroup.

(Step 12)

This step is a reaction for deprotecting the protecting group P′″ of thecompound of the formula (XVIII′). As for the method for deprotection, itcan be performed by a generally known method, for example, the methoddescribed in Protective Groups in Organic Synthesis, T. W. Greene, JohnWiley & Sons (1981) or a method similar to it. Examples of theprotecting group P′″ include a tert-butoxycarbonyl group, ap-methoxycarbobenzoxy group, and a trityl group. It is preferably atert-butoxycarbonyl group.

When the protecting group P′″ is a tert-butoxycarbonyl group,deprotection can be achieved by using an acid. The solvent used for thereaction of this step is not particularly limited as long as it does notcause any problem on the reaction. Examples of the solvent includechloroform, dichloromethane, dioxane, THF, ethyl acetate, methanol, andwater. Furthermore, examples of the acid used for this step includemineral acid such as hydrochloric acid and sulfuric acid and an organicacid such as trifluoroacetic acid and paratoluenesulfonic acid.Temperature for the reaction is 0 to 100° C., and preferably roomtemperature to 60° C. The time of the reaction is 1 to 48 hours,preferably a 1 to 6 hours. The compound of the formula (XIX) obtained bythis step can be separated and purified by a known means for separationand purification, for example, concentration, concentration underreduced pressure, re-precipitation, solvent extraction, crystallization,and chromatography, or it can be subjected to the next step without anyseparation and purification.

(Step 13)

This step relates to a method for producing the compound represented bythe formula (XXI) by using the compound represented by the formula(XIX). The reaction of this step can be performed by using sulfonylchloride represented by the formula (XX) in an aprotic solvent in thepresence of a base. The amount of the compound represented by theformula (XX) which is used is, relative to 1 eqv. of the compound of theformula (XIX), 0.5 to 5 eqv., and preferably 1 to 3 eqv. Examples of thebase include triethylamine, diisopropylethylamine, pyridine, DMAP, andDBU. It is preferably triethylamine. The solvent which can be used forthis step is not particularly limited as long as it does not cause anyproblem on the reaction. Examples of the solvent include THF, dioxane,diethyl ether, chloroform, dichloromethane, toluene, and DMF. It ispreferably dichloromethane. The reaction temperature is 0 to 100° C.,and preferably 0 to 50° C. The time of the reaction is 0.5 to 48 hours,and preferably 1 to 6 hours. The compound of the formula (XXI) obtainedby this step can be separated and purified by a known means forseparation and purification, for example, concentration, concentrationunder reduced pressure, re-precipitation, solvent extraction,crystallization, and chromatography.

The tetrahydropyridopyrimidine compound represented by the generalformula (I) (hereinbelow, it may be also referred to as the “compound ofthe formula (I) of the present invention”), which is obtained by theprocess described above, may have an optical isomer or a geometricisomer depending on the type of a substituent group, and any of those isalso included in the compound of the formula (I) of the presentinvention. The isomers may be subjected to resolution or used as amixture of the isomers by themselves. Furthermore, tautomers shown beloware present for the tetrahydropyridopyrimidine compound represented bythe general formula (I), and any of those tautomers is also included inthe compound of the formula (I) of the present invention.

Furthermore, a solvate represented by a hydrate, a non-crystalline(amorphous) or crystalline polymorph is also encompassed by the compoundof the formula (I) of the present invention.

The compound of the formula (I) of the present invention may form a saltaccording to a commonly known method. As for the type of the salt of thecompound of the formula (I) of the present invention, any of theaforementioned pharmaceutically acceptable salts is possible.

The compound of the formula (I) of the present invention or a saltthereof can be separated and purified by a known means for separationand purification, for example, concentration, solvent extraction,filtration, recrystallization, or various chromatographies.

When the compound of the formula (I) of the present invention or apharmaceutically acceptable salt thereof is used as a pharmaceuticalagent, various administration forms can be adopted depending on purposeof prevention or treatment. Examples of the administration form includeoral and parenteral administration forms, for example, an oralpreparation, an injection, a suppository, an external preparation, and apatch. Preferably, an oral preparation is used. Each of thoseadministration forms can be produced by a formulation method that isgenerally known to a person skilled in the art.

The pharmaceutical agent can be a pharmaceutical composition containingan effective amount of the compound of the formula (I) of the presentinvention or a pharmaceutically acceptable salt, and a pharmaceuticallyacceptable carrier. As for the pharmaceutically acceptable carrier,various organic or inorganic carrier substances that are generally usedas a material for formulation are used, and for a solid formulation, forexample, there may be mentioned a vehicle, a lubricating agent, abinding agent, and a disintegrating agent, and for a liquid formulation,there may be mentioned a solvent, a dissolution aid, a suspending agent,an isotonic agent, a buffer agent, a stabilizing agent, a pH controllingagent, a surfactant, a wetting agent, a preservative, and a painrelieving agent. Furthermore, the pharmaceutical agent may containformulation additives such as a preservative, an anti-oxidant, acoloring agent, a sweetening agent, and a flavoring agent, if necessary.

The pharmaceutically acceptable carrier or formulation additives can bethose that are generally used in the pertinent field. Examples of thevehicle include lactose, white sugar, sodium chloride, glucose, starch,calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid;examples of the binding agent include water, ethanol, propanol, sweetsyrup, glucose solution, starch solution, gelatin solution,carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch,methyl cellulose, ethyl cellulose, shellac, calcium phosphate, andpolyvinylpyrrolidone; examples of the disintegrating agent include drystarch, sodium alginate, agar powder, sodium hydrogen carbonate, calciumcarbonate, sodium lauryl sulfate, stearic acid monoglyceride, andlactose; examples of the lubricating agent include purified talc,stearic acid salt, borax, and polyethylene glycol; examples of thecoloring agent include titanium oxide and iron oxide; and examples ofthe flavoring agent include white sugar, orange peel, citric acid, andtartaric acid.

For producing a solid formulation for oral administration, the compoundof the formula (I) of the present invention or a pharmaceuticallyacceptable salt thereof is added with a vehicle, and if necessary, witha binding agent, a disintegrating agent, a lubricating agent, a coloringagent, a flavoring agent, or the like, and prepared as a tablet, acoated tablet, a granule, a powder, or a capsule, for example, accordingto a commonly used method.

For producing a liquid formulation for oral administration, the compoundof the formula (I) of the present invention or a pharmaceuticallyacceptable salt thereof is added with a flavoring agent, a buffer agent,a stabilizing agent, a corrigent, or the like, and prepared as ainternal liquid medicine, a syrup, or an elixir, for example. In thatcase, the flavoring agent may be the same as those described above;examples of the buffer agent include sodium citrate; and examples of thestabilizing agent include tragacanth, gum Arabic, and gelatin.

For producing an injection, the compound of the formula (I) of thepresent invention or a pharmaceutically acceptable salt thereof is addedwith a pH controlling agent, a buffer agent, a stabilizing agent, anisotonic agent, a local anesthetic, or the like, and prepared as anintramuscular or intravenous injection according to a commonly usedmethod. In that case, examples of the pH controlling agent and bufferagent include sodium citrate, sodium acetate, and sodium phosphate;examples of the stabilizing agent include sodium pyrosulfite, EDTA,thioglycolic acid, and thiolactic acid; examples of the local anestheticinclude procaine hydrochloride and lidocaine hydrochloride; and examplesof the isotonic agent include sodium chloride and glucose.

For producing a suppository, the compound of the formula (I) of thepresent invention or a pharmaceutically acceptable salt thereof is addedwith a known carrier for formulation, e.g., polyethylene glycol,lanolin, kakao fat, and a fatty acid triglyceride, and if necessary, asurfactant such as Tween (registered trademark), and production isperformed according to a common method.

For producing an external preparation such as an ointment, a cream, agel, or a paste, the compound of the formula (I) of the presentinvention or a pharmaceutically acceptable salt thereof is added with,if necessary, a commonly used base, a stabilizing agent, a wettingagent, or a preservative, and mixing and formulating are performedaccording to a common method. Examples of the base include fluidparaffin, white vaseline, white beeswax, octyl dodecyl alcohol, andparaffin. Examples of the preservative include methyl paraoxybenzoate,ethyl paraoxybenzoate, and propyl paraoxybenzoate.

For producing a patch, the ointment, cream, gel, or paste, for example,are coated on a common support according to a common method. Examples ofthe support include a woven or non-woven fabric consisting of cotton,staple fiber, or chemical fiber, or a film or a foamed sheet of softvinyl chloride, polyethylene, and polyurethane.

The amount of the compound of the formula (I) of the present inventionor a pharmaceutically acceptable salt thereof which needs to be blendedin each administration unit form described above varies depending onsymptom, weight, age, or sex of a subject for application, or aformulation type, for example. However, in terms of the amount of thecompound of the formula (I) of the present invention, it is preferably0.05 to 1000 mg for an oral preparation, 0.01 to 500 mg for aninjection, and 1 to 1000 mg for a suppository. Furthermore, the dailydose of above administration form varies depending on species, symptom,weight, age, or sex of a subject for application. However, in terms ofthe amount of the compound of the formula (I) of the present invention,it is preferably 0.05 to 5000 mg, and preferably 0.1 to 1000 mg per dayfor an adult, and it is preferably administered once or in about 2 to 4divided doses per day. With regard to the compound of the formula (I) ofthe present invention or a pharmaceutically acceptable salt, any onetype of the compound or a salt may be used singly or a plurality oftypes may be used in combination.

As described herein, the anti-androgen activity means an activity ofsuppressing the androgen activity, and a compound, a composition, or apharmaceutical agent having the anti-androgen activity is referred to asan anti-androgen agent. The compound of the formula (I) of the presentinvention or a pharmaceutically acceptable salt thereof acts as anantagonist for an androgen receptor (AR) and suppresses the response ofAR to androgen, thus exhibiting the anti-androgen activity. Furthermore,as the compound of the formula (I) of the present invention or a saltthereof also has an activity of lowering AR expression, it can exhibitan anti-androgen activity based on it. By having the anti-androgenactivity, the compound of the formula (I) of the present invention or apharmaceutically acceptable salt thereof exhibits the effect ofsuppressing an occurrence or progress of various disorders, anoccurrence of tumor, or progress or recurrence of a progressive orrecurrent tumor.

Thus, according to another embodiment, provided by the present inventionis an anti-androgen agent which contains, as an active ingredient, thecompound of the formula (I) of the present invention or apharmaceutically acceptable salt. Also provided by the present inventionis use of the compound of the formula (I) of the present invention or apharmaceutically acceptable salt thereof for producing an anti-androgenagent. Also provided by the present invention is use of the compound ofthe formula (I) of the present invention or a pharmaceuticallyacceptable salt thereof as an anti-androgen agent. Also provided by thepresent invention is the compound of the formula (I) of the presentinvention or a pharmaceutically acceptable salt thereof for use as ananti-androgen agent.

According to another embodiment, provided by the present invention is apharmaceutical agent which contains, as an active ingredient, thecompound of the formula (I) of the present invention or apharmaceutically acceptable salt. Also provided by the present inventionis use of the compound of the formula (I) of the present invention or apharmaceutically acceptable salt thereof for producing a pharmaceuticalagent. Also provided by the present invention is use of the compound ofthe formula (I) of the present invention or a pharmaceuticallyacceptable salt thereof as a pharmaceutical agent. Also provided by thepresent invention is the compound of the formula (I) of the presentinvention or a pharmaceutically acceptable salt thereof for use as apharmaceutical agent.

According to another embodiment, provided by the present invention is apharmaceutical composition which contains the compound of the formula(I) of the present invention or a pharmaceutically acceptable salt, anda pharmaceutically acceptable carrier.

According to a preferred embodiment, the pharmaceutical agent orpharmaceutical composition is used as an anti-androgen agent.Furthermore, according to a preferred embodiment, the pharmaceuticalagent or pharmaceutical composition is a therapeutic agent for adisorder related with AR activation. Furthermore, according to apreferred embodiment, the pharmaceutical agent or pharmaceuticalcomposition is an anti-tumor agent.

Meanwhile, according to another embodiment, provided by the presentinvention is a method of suppressing androgen activity includingadministering an effective amount of the compound of the formula (I) ofthe present invention or a pharmaceutically acceptable salt thereof to asubject. Also provided by the present invention is a method for treatinga disorder related with AR activation including administering aneffective amount of the compound of the formula (I) of the presentinvention or a pharmaceutically acceptable salt thereof to a subject.Also provided by the present invention is a method for treating tumorincluding administering an effective amount of the compound of theformula (I) of the present invention or a pharmaceutically acceptablesalt thereof to a subject.

With regard to a method for suppressing androgen activity, a method fortreating a disorder related with AR activation, and a method fortreating tumor according to the present invention, examples of thesubject include a human or a non-human animal in need of the method.Examples of the non-human animal include primates such as a monkey and achimpanzee, and mammals such as a mouse, a rat, a hamster, a guinea pig,a dog, a cat, a cow, a horse, a sheep, a goat, and a pig; however, it isnot limited thereto.

The effective amount or administration regimen of the compound of theformula (I) of the present invention or a pharmaceutically acceptablesalt thereof administered to the above subject can be suitablydetermined by a person skilled in the art depending on, for example,species, symptom, weight, age, or sex, of the subject. For example, whenthe subject is an adult human, it is usually administered at 0.05 to5000 mg, and preferably 0.1 to 1000 mg per day in terms of the amount ofthe compound of the formula (I) of the present invention, and it ispreferably administered once or in about 2 to 4 divided doses per day.

Examples of the disorder related with AR activation include tumor,metastatic bone disease, prostatic hyperplasia, acne vulgaris,seborrhea, hypertrichosis, androgenetic alopecia, precocious puberty,and virillizing syndrome. Examples of the tumor include prostate cancer,breast cancer, ovarian cancer, bladder cancer, uterine cancer,pancreatic cancer, and hepatocellular cancer. It is preferably prostatecancer. Meanwhile, the tumor also includes resistant, recurrent, ormetastatic tumor. Thus, specific examples of the prostate cancerinclude, in addition to common prostate cancer, castration resistantprostate cancer (CRPC), hormone resistant prostate cancer (HRPC), PSArecurrent prostate cancer, taxan resistant prostate cancer, andradiation resistant prostate cancer. It is preferably castrationresistant prostate cancer.

Examples of a conventional anti-androgen agent include bicalutamide.However, as they have an agonist activity for AR, the effect is notmaintained for a long period of time, and recurrent cancer is observed 2to 5 years after the response. Furthermore, in CRPC, overexpression ofAR is believed to be a cause of recurrence. The compound of the formula(I) of the present invention or a salt thereof has a potent antagonistactivity for AR but no agonist activity therefor, and it exhibits astrong AR antagonist activity for cells in which AR is overexpressed.Furthermore, by having the activity of reducing AR expression inaddition to the antagonist activity for AR, the compound of the formula(I) of the present invention or a salt thereof is effective for cancerhaving overexpressed AR such as CRPC.

EXAMPLES

Hereinbelow, the present invention is described specifically by way ofExamples and Test Examples. However, they are described solely forexemplification, and the scope of the present invention is not limitedto them.

Production Example

For the following examples given below, various reagents used werecommercially available products, unless specifically describedotherwise. For silica gel column chromatography, Purif-Pack (registeredtrademark) SI manufactured by MORITEX Corporation, KP-Sil (registeredtrademark) Silica pre-packed column manufactured by Biotage, or HP-Sil(registered trademark) Silica pre-packed column manufactured by Biotagewere used. For basic silica gel column chromatography, Purif-Pack(registered trademark) NH manufactured by MORITEX Corporation or KP-NH(registered trademark) pre-packed column manufactured by Biotage wereused. For basic silica gel column chromatography, Purif-Pack (registeredtrademark) NH manufactured by MORITEX Corporation or KP-NH (registeredtrademark) pre-packed column manufactured by Biotage were used.

Reverse phase preparative HPLC column chromatography was performed atthe following conditions.Column: YMC-Actus Triart C18 manufactured by YMC, 30×50 mm, 5 μmUV detection: 254 nmColumn flow rate: 40 mL/minMobile phase: water/acetonitrile (0.1% formic acid)Injection volume: 1.0 mLGradient water/acetonitrile 10%→60% (7 minutes)

For ¹H-NMR spectrum measurement, AL400 (400 MHz; JEOL Ltd. (JEOL)),Mercury400 (400 MHz; Agilent Technologies, Inc.) type spectrometer, orInova400 (400 MHz; Agilent Technologies, Inc.) type spectrometerequipped with OMNMR probe (Protasis) was used. For obtaining ¹H-NMRspectrum, measurement was made using TMS (tetramethylsilane) as aninternal standard, and chemical shift was represented in terms of δvalue (ppm). With regard to the chemical shift, number of protons,absorption pattern, and coupling constant (J value) were described inparentheses. With regard to the absorption pattern, the followingsymbols were used: s=singlet, d=doublet, t=triplet, q=quartet,sept=septet, dd=double doublet, dt=double triplet, dq=double quartet,m=multiplet, br-s=broad singlet.

For mass spectrum, low resolution mass spectrometer (LRMS) was used, andthe measurement was performed by electrospray ionization method(hereinbelow, ESI).

With regard to the structural formula of compounds, the followingsymbols may be used: Me=methyl, Et=ethyl, tBu=tert-butyl, Ph=phenyl,Bn=benzyl, Ac=acetyl, Boc=tert-butoxy carbonyl, TFA=trifluoroaceticacid, MsOH=methanesulfonic acid.

With regard to the solvent and reagent, the following abbreviations maybe used:

DMSO=dimethyl sulfoxide;

DMF=N,N-dimethylformamide;

THF=tetrahydrofuran;dba=dibenzylideneacetone;dppf=1,1-bis(diphenylphosphino)ferrocene;XantPhos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;Boc₂O=di-tert-butyl dicarbonate;DMAP=4-dimethylaminopyridine;TFA=trifluoroacetic acid;DIPEA=diisopropylethylamine;DMT-MM=4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinumchloride;HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate;HOBt=1-hydroxybenzotriazole;WSC=EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;DBU=1,8-diazabicyclo[5,4,0]undecene;NMP=N-methyl-2-pyrrolidone;DMA=dimethylacetamide;DCC=N,N′-dicyclohexylcarbodiimide;DPPA=diphenylphosphoryl azide;LDA=lithium diisopropylamide.

Reference Example 1-14-(4-Hydroxy-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Commercially available7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (12.6 g), 10%palladium/carbon (2 g), and ammonium formate (16.5 g) were suspended inmethanol (200 mL), followed by stirring overnight at 60° C. The reactionsolution was filtered through Celite and concentrated, and then used forthe next reaction without any purification. It was suspended with4-fluoro-2-(trifluoromethyl)benzonitrile (10 g) in DMSO (150 mL) andstirred overnight at room temperature. The reaction solution was addedwith water (200 mL) and the solid was separated by filtering. It wasfurther suspended and washed with 100 mL of ethyl acetate, followed bydrying by heating to obtain the target compound (7.1 g).

¹H-NMR (DMSO-d₆) δ12.35 (1H, br-s), 8.09 (1H, S), 7.85 (1H, d, J=8.0Hz), 7.39 (1H, s), 7.32 (1H, d, J=8.0 Hz), 4.34 (2H, s), 3.71 (2H, t,J=4.0), 2.56 (2H, t, J=4.0 Hz); LRMS (ESI) m/z 321 [M+H]⁺.

Reference Example 1-24-(4-Chloro-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The solid (12.3 g) obtained from Reference Example 1-1 was suspended indichloroethane (60 mL), and added with phosphorus oxychloride (36 mL)and triethylamine (12 mL), followed by stirring for 30 minutes at 90° C.The reaction solution was added to water (300 mL) and extracted withchloroform (300 mL×three times) of which pH had been adjusted to 7 usingsodium carbonate. After drying over magnesium sulfate, it wasconcentrated, and suspended and washed with ethyl acetate to obtain 9.4g (72%) of the target compound.

¹H-NMR (DMSO-d₆) δ8.89 (1H, s), 7.89 (1H, d, J=8.0 Hz), 7.47 (1H, s),7.40 (1H, d, J=8.0 Hz), 4.73 (2H, s), 3.90 (2H, t, J=4.0), 2.94 (2H, t,J=4.0 Hz); LRMS (ESI) m/z 339 [M+H]⁺.

Reference Example 1-32-Chloro-4-(4-chloro-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

Commercially available 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-olhydrochloride (10.0 g), 2-chloro-4-fluorobenzonitrile (8.1 g), andtriethylamine (22 mL) were added to DMSO (183 mL) and stirred for 2 daysat room temperature. After adding water (400 mL), the reaction solutionwas adjusted to have a pH of 4 to 6 using conc. hydrochloric acid, andthe precipitated solid was collected by filtration. The obtained solidwas suspended and washed with ethyl acetate followed by drying. It wasused for the next reaction without purification. The obtained solid (6.4g) was refluxed for 10 minutes in phosphorus oxychloride (15 mL). Afterconcentration under reduced pressure, it was added with water (400 mL)and the aqueous layer was adjusted to have a pH of 8 by using sodiumcarbonate. The precipitated solid was collected by filtration, followedby drying. It was suspended and washed with toluene to obtain 5.8 g (twostep yield 47%) of the target compound.

¹H-NMR (DMSO-d₆) δ8.87 (1H, s), 7.70 (1H, d, J=8.9 Hz), 7.32 (1H, d,J=2.3 Hz), 7.12 (1H, dd, J=8.9, 2.3 Hz), 4.66 (2H, s), 3.83 (2H, t,J=5.8 Hz), 2.90 (2H, t, J=5.8 Hz); LRMS (ESI) m/z 306 [M+H]⁺.

Reference Example 2-1 Methyl6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinate

The compound (10.0 g) obtained from Reference Example 1-2, methyl6-aminonicotinate (4.49 g), Pd(dba)₂ (1.70 g), dppf (1.64 g), and cesiumcarbonate (24.1 g) were suspended in dioxane (120 mL) and stirredovernight at 80° C. under nitrogen atmosphere. The reaction solution wascooled to room temperature, and the solid obtained by adding water wascollected by filtration, and purified by silica gel columnchromatography to obtain 9.42 g (70%) of the target compound.

¹H-NMR (DMSO-d₆) δ9.63 (1H, s), 8.82 (1H, s), 8.65 (1H, s), 8.27-8.21(2H, m), 7.85 (1H, d, J=8.8 Hz), 7.42 (1H, d, J=2.0 Hz), 7.35 (1H, dd,J=8.8, 2.0 Hz), 4.57 (2H, s), 3.85-3.80 (5H, m), 2.91 (2H, t, 5.2 Hz);LRMS (ESI) m/z 455 [M+H]⁺.

Reference Example 2-26-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinicacid

The compound (9.21 g) obtained from Reference Example 2-1 was suspendedin methanol (100 mL), and added with 5.0 mol/L aqueous solution ofsodium hydroxide (11 mL), followed by stirring overnight at 40° C. Thereaction solution was cooled to room temperature, and the pH wasadjusted to about 3 by using 5.0 mol/L hydrochloric acid. Theprecipitated solid was collected by filtration, and after washing withdistilled water and air drying, 8.24 g (92%) of the target compound wasobtained. The compound was directly used for the next step withoutperforming any purification.

¹H-NMR (DMSO-d₆) δ9.59 (1H, s), 8.83 (1H, d, J=2.0 Hz), 8.67 (1H, s),8.27-8.23 (2H, m), 7.87 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=2.0 Hz), 7.38(1H, dd, J=2.4, 8.8 Hz), 4.60 (2H, s), 3.86 (2H, t, J=5.6 Hz), 2.93 (2H,t, J=5.6 Hz); LRMS (ESI) m/z 441 [M+H]⁺.

Reference Example 3 2-(6-Aminopyridin-3-yl)propan-2-ol

Methyl 6-aminonicotinate (5.0 g) was suspended in THF (500 mL), andadded with methyl lithium at −78° C., followed by stirring for 15 hourswhile the temperature was naturally increased. The reaction mixture wasadded with a saturated aqueous solution of ammonium chloride in an icebath, and extraction was performed 3 times with chloroform/methanol=5/1.The organic layer was combined together, and dried over anhydrous sodiumsulfate. The insoluble matters were separated by filtration, and thefiltrate was concentrated and dried. The obtained solid was purified bysilica gel column chromatography to obtain 2.2 g (44%) of the targetcompound.

¹H-NMR (DMSO-d₆) δ7.97 (1H, d, J=2.4 Hz), 7.43 (1H, dd, J=8.8, 2.4 Hz),6.36 (1H, d, J=8.8 Hz), 5.66 (2H, br-s), 4.82 (1H, s), 1.36 (6H, s);LRMS (ESI) m/z 153 [M+H]⁺.

Production Example A 2-(6-Aminopyridazin-3-yl)propan-2-ol Step 1Synthesis of ethyl 6-aminopyridazine-3-carboxylate

To ethanol (800 mL), sodium (7.2 g) was slowly added and stirred for 2hours at room temperature. After confirming that all sodium wasdissolved, commercially available methyl 6-aminopyridazine-3-carboxylate(40.0 g) was added and further stirred at room temperature for 1 hour.To the reaction solution, hydrogen chloride (4.0 mol/L ethyl acetatesolution, about 80 mL) was added in dropwise manner to adjust the pH toabout 5. The obtained reaction solution was concentrated and dried, andafter suspending and washing with distilled water followed by collectingby filtration and air drying, 39.9 g (99%) of the target compound wasobtained.

¹H-NMR (DMSO-d₆) δ7.73 (1H, d, J=9.2 Hz), 7.14 (2H, br-s), 6.77 (1H, d,J=9.2 Hz), 4.29 (2H, q, J=7.2 Hz), 1.29 (3H, t, J=7.2 Hz); LRMS (ESI)m/z 168 [M+H]⁺.

Step 2 Synthesis of 2-(6-aminopyridazin-3-yl)propan-2-ol

By performing the same operation as Reference Example 3 and using thecompound (4.00 g) obtained from step 1 instead of methyl6-aminonicotinate, 1.21 g (33%) of the target compound was obtained asan oily product.

¹H-NMR (DMSO-d₆) δ7.45 (1H, d, J=9.2 Hz), 6.73 (1H, d, J=9.2 Hz), 6.14(2H, br-s), 5.12 (1H, s), 1.41 (6H, s); LRMS (ESI) m/z 154 [M+H]⁺.

Production Example B6-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridazine-3-carboxylicacid Step 1 Synthesis of methyl6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridazine-3-carboxylate

By performing the same operation as Reference Example 2-1 and using acommercially available methyl 6-aminopyridazine-3-carboxylate (100 mg)instead of methyl 6-aminonicotinate, 38 mg (28%) of the target compoundwas obtained.

¹H-NMR (DMSO-d₆) δ10.39 (1H, s), 8.65 (1H, s), 8.48 (1H, d, J=9.6 Hz),8.16 (1H, d, J=9.6 Hz), 7.86 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=2.8 Hz),7.37 (1H, dd, J=8.8, 2.0 Hz), 4.60 (2H, s), 3.91 (3H, s), 3.85 (2H, t,J=6.0 Hz), 2.97 (2H, t, 5.6 Hz); LRMS (ESI) m/z 456 [M+H]⁺.

Step 2 Synthesis of6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridazine-3-carboxylicacid

By performing the same operation as Reference Example 2-2 and using thecompound (2.30 g) obtained from step 1 instead of the compound obtainedfrom Reference Example 2-1, 2.04 g (91%) of the target compound wasobtained.

¹H-NMR (DMSO-d₆) δ10.32 (1H, s), 8.64 (1H, s), 8.45 (1H, d, J=9.6 Hz),8.13 (1H, d, J=9.2 Hz), 7.86 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=2.4 Hz),7.37 (1H, dd, J=8.8, 2.4 Hz), 4.60 (2H, s), 3.85 (2H, t, J=5.6 Hz), 2.97(2H, t, 6.0 Hz); LRMS (ESI) m/z 442 [M+H]⁺.

Production Example C5-((7-4-Cyano-3-(trifluoromethyl)phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyrazine-2-carboxylicacid Step 1 Synthesis of5-((7-4-cyano-3-(trifluoromethyl)phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyrazine-2-carboxylicacid methyl ester

By performing the same operation as Reference Example 2-1 and using thecompound (700 mg) obtained from Reference Example 1-2 and5-aminopyrazine-2-carboxylic acid methyl ester (320 mg) instead ofmethyl 6-aminonicotinate, 360 mg (38%) of the target compound wasobtained (yield 66%).

¹H-NMR (CDCl₃) δ9.99 (1H, s), 8.99 (1H, s), 8.79 (1H, s), 7.70 (1H, d,J=8.8 Hz), 7.56 (1H, s), 7.09 (1H, dd, J=2.6 Hz, 8.9 Hz), 4.57 (2H, s),4.03 (3H, s), 3.90 (2H, t, J=5.7 Hz), 2.94 (2H, t, 5.5 Hz); LRMS (ESI)m/z 456 [M+H]⁺.

Step 2 Synthesis of5-((7-4-cyano-3-(trifluoromethyl)phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyrazine-2-carboxylicacid

By performing the same operation as Reference Example 2-2 for thecompound (360 mg) obtained from step 1, 310 mg of the target compoundwas obtained (yield 89%).

¹H-NMR (DMSO-d₆) δ10.06 (1H, br-s), 9.39 (1H, s), 8.92 (1H, s), 8.70(1H, s), 7.89 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=2.2 Hz), 7.40 (1H, dd,J=2.7 Hz, 9.0 Hz), 4.63 (2H, s), 3.87 (2H, t, J=5.6 Hz), 2.94 (2H, m);LRMS (ESI) m/z 442 [M+H]⁺.

Production Example D2-((7-4-Cyano-3-(trifluoromethyl)phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyrimidine-5-carboxylicacid Step 1 Synthesis of 2-aminopyrimidine-5-carboxylic acid methylester

3,3-Dimethoxy-2-methoxycarbonylpropen-1-ol sodium salt (3.0 g), whichhad been synthesized according to the method described in Synthesis,2002, 6, 720, and guanidine hydrochloride were dissolved in DMF (24 mL)and stirred at 100° C. for 1 hour. After cooling to room temperature,water was added to precipitate a solid, which was then collected byfiltration and dried under reduced pressure to obtain 720 mg (30%) ofthe target compound.

¹H-NMR (DMSO-d₆) δ8.69 (2H, s), 7.57 (2H, s), 3.78 (3H, s); LRMS (ESI)m/z 154 [M+H]⁺.

Step 2 Synthesis of methyl2-((7-4-cyano-3-(trifluoromethyl)phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyrimidine-5-carboxylate

By performing the same operation as Reference Example 2-1 and using thecompound (300 mg) obtained from Reference Example 1-2 and5-2-aminopyrimidine-5-carboxylic acid methyl ester (164 mg) obtainedfrom step 1 instead of methyl 6-aminonicotinate, 128 mg of the targetcompound was obtained (yield 32%).

¹H-NMR (CDCl₃) δ9.11 (2H, s), 8.94 (1H, s), 8.01 (1H, s), 7.71 (1H, d,J=8.8 Hz), 7.23 (1H, s), 7.07 (1H, d, J=8.8 Hz), 4.63 (2H, s), 3.97 (3H,s), 3.78 (2H, t, J=5.7 Hz), 2.92 (2H, t, 5.5 Hz); LRMS (ESI) m/z 456[M+H]⁺.

Step 3 Synthesis of2-((7-4-cyano-3-(trifluoromethyl)phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyrimidine-5-carboxylicacid

By performing the same operation as Reference Example 2-2 for thecompound (120 mg) obtained from step 2, 114 mg of the target compoundwas obtained (yield 99%).

¹H-NMR (DMSO-d₆) δ10.65 (1H, s), 8.94 (2H, m), 8.82 (1H, s), 7.88 (1H,d, J=8.8 Hz), 7.43 (1H, s), 7.36 (1H, d, J=9.0 Hz), 4.69 (2H, s), 3.78(2H, t, J=5.5 Hz), 2.77 (2H, m); LRMS (ESI) m/z 442 [M+H]⁺.

Production Example E5-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-1,3,4-thiadiazol-2-carboxylicacid

By performing the same operation as Reference Examples 2-1 and 2-2 andusing ethyl 5-amino-1,3,4-thiadiazol-2-carboxylate (92 mg) instead ofmethyl 6-aminonicotinate, 141 mg of the target compound was obtained(two step yield 72%).

¹H-NMR (DMSO-d₆) δ8.80 (1H, s), 7.88 (1H, d, J=8.4 Hz), 7.46 (1H, br-s),7.39 (1H, d, J=8.4 Hz), 4.62 (2H, s), 3.88 (2H, t, J=5.2 Hz), 2.97 (2H,t, J=5.2 Hz); LRMS (ESI) m/z 448 [M+H]⁺.

Example 14-(4-((1,2,4-Thiadiazol-5-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thecompound (100 mg) obtained from Reference Example 1-2,5-amino-1,2,4-thiadiazole (45 mg) instead of methyl 6-aminonicotinate,Pd₂(dba)₃ (30 mg) instead of Pd(dba)₂, and Xantphos (17 mg) instead ofdppf, 10 mg of the target compound was obtained (yield 8%).

¹H-NMR (DMSO-d₆) δ8.88 (1H, s), 8.31 (1H, s), 7.71 (1H, d, J=8.8 Hz),7.26 (1H, s), 7.10 (1H, d, J=8.8 Hz), 4.59 (2H, s), 3.89 (2H, t, J=5.9Hz), 2.96 (2H, t, J=5.9 Hz); LRMS (ESI) m/z 404 [M+H]⁺.

Example 24-(4-((4-Isopropoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (19 mg) obtained from Reference Example 1-2 and4-isopropoxyaniline (10 mg) were dissolved in acetonitrile (1.5 mL) andreacted for 10 minutes at 180° C. under irradiation of microwave. Afterconcentrating the solvent, it was purified by silica gel columnchromatography to obtain the target compound (17 mg, 60%).

¹H-NMR (CDCl₃) δ8.55 (1H, s), 7.69 (1H, d, J=8.7 Hz), 7.45-7.36 (2H, m),7.24 (1H, d, J=2.4 Hz), 7.06 (1H, dd, J=8.7, 2.4 Hz), 6.96-6.88 (2H, m),6.31 (1H, s), 4.53 (1H, sept, J=6.1 Hz), 4.48 (2H, s), 3.87 (2H, t,J=6.1 Hz), 2.75 (2H, t, J=5.7 Hz), 1.35 (6H, d, J=6.1 Hz); LRMS (ESI)m/z 454 [M+H]⁺.

Example 34-(4-((4-Methoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The solid (600 mg) obtained from Reference Example 1-2 and p-anisidine(262 mg) were suspended in acetonitrile (12 mL) and stirred for 20minutes at 180° C. under irradiation of microwave. The obtained reactionsolution was concentrated and dried, followed by purification by silicagel column chromatography to obtain the target compound (555 mg).

¹H-NMR (DMSO-d₆) δ9.89 (1H, br-s), 8.68 (1H, s), 7.96 (1H, d, J=8.0 Hz),7.48-7.42 (3H, m), 7.37 (1H, dd, J=8.0, 4.0 Hz), 6.99 (1H, d, J=20.0Hz), 4.68 (2H, s), 3.93 (2H, t, J=4.0 Hz), 3.17 (3H, s), 2.83 (2H, t,4.0 Hz); LRMS (ESI) m/z 426 [M+H]⁺.

Example 44-(4-((1,1′-Biphenyl)-3-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The solid (100 mg) obtained from Reference Example 1-2 and3-aminobiphenyl (125 mg) were suspended in acetonitrile (2.0 mL), andadded with potassium carbonate (182 mg), followed by stirring for 8hours at 80° C. The obtained reaction solution was concentrated anddried, followed by purification by silica gel column chromatography toobtain the target compound (15 mg).

¹H-NMR (DMSO-d₆) δ8.63 (1H, s), 8.46 (1H, s), 7.95 (1H, t, J=2.0 Hz),7.87 (1H, d, J=9.3 Hz), 7.75 (1H, d, J=8.3 Hz), 7.67-7.62 (2H, m),7.51-7.33 (7H, m), 4.53 (2H, s), 3.91 (2H, t, J=5.6 Hz), 2.84 (2H, t,5.6 Hz); LRMS (ESI) m/z 472 [M+H]⁺.

Example 54-(4-((6-Fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of 5-bromo-6-fluoropyridin-2-amine

6-Fluoropyridin-2-amine (2.40 g) was dissolved in acetonitrile (45 mL),and under light blocking conditions, N-bromosuccinimide (3.81 g) wasadded under ice cooling, followed by stirring for 3 days and nights atroom temperature under light blocking conditions. The obtained reactionsolution was concentrated and dried, followed by purification by silicagel column chromatography to obtain 3.22 g (79%) of the target compound.

¹H-NMR (CDCl₃) δ7.61 (1H, t), 6.27 (1H, dd, J=8.4, 0.8 Hz), 4.63 (2H,br-s); LRMS (ESI) m/z 191 [M+H]⁺.

Step 2 Synthesis of methyl 6-amino-2-fluoronicotinate

The solid (500 mg) obtained from step 1, palladium acetate (II) (118mg), dppf (290 mg), and triethylamine (1.1 mL) were suspended inmethanol (10 mL) and N,N-dimethylformamide (30 mL), and under atmosphereof carbon monoxide (0.4 MPa), stirred for 18 hours at 75° C. Thereaction solution was filtered through Celite and concentrated underreduced pressure. The obtained oily product was dissolved in ethylacetate and washed with distilled water and saturated brine, followed bydrying over anhydrous sodium sulfate. The insoluble matters wereseparated by filtration, and the filtrate was concentrated and dried.The obtained solid was purified by silica gel column chromatography toobtain 133 mg (30%) of the target compound.

¹H-NMR (DMSO-d₆) δ7.91 (1H, dd, J=10.0, 8.4 Hz), 7.22 (2H, br-s), 6.34(1H, dd, J=8.8, 2.0 Hz), 3.73 (3H, s); LRMS (ESI) m/z 171 [M+H]⁺.

Step 3 Synthesis of 2-(6-amino-2-fluoropyridin-3-yl)propan-2-ol

The solid (200 mg) obtained from step 2 was dissolved in tetrahydrofuran(4 mL) and added with methyl magnesium bromide (3.0 mol/Ltetrahydrofuran solution, 1.96 mL) under ice cooling, followed bystirring for 5 hours. The reaction solution was added with a saturatedaqueous solution of ammonium chloride, and extracted with ethyl acetate.The organic layer was washed with distilled water and saturated brine,followed by drying over anhydrous magnesium sulfate. The insolublematters were separated by filtration, and the filtrate was concentratedunder reduced pressure. The obtained oily product was purified by silicagel column chromatography to obtain 32 mg (16%) of the target compoundas an oily product. The compound was used directly for the next stepwithout performing any further purification.

LRMS (ESI) m/z 171 [M+H]⁺.

Step 4 Synthesis of4-(4-((6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using theoily product obtained from step 3 instead of methyl 6-aminonicotinate,25 mg (30%) of the target compound was obtained.

¹H-NMR (DMSO-d₆) δ9.25 (1H, s), 8.56 (1H, s), 8.04-7.97 (2H, m), 7.83(1H, d, J=8.8 Hz), 7.41 (1H, d, J=2.4 Hz), 7.34 (1H, dd, J=8.8, 2.0 Hz),5.32 (1H, s), 4.53 (2H, s), 3.82 (2H, t, J=5.2 Hz), 2.84 (2H, t, 5.6Hz), 1.44 (6H, s); LRMS (ESI) m/z 473 [M+H]⁺.

Example 62-Chloro-4-(4-((6-(2-hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thesolid (1.85 g) obtained from Reference Example 1-3 instead of thecompound obtained from Reference Example 1-2 and the oily product (975mg) obtained from Production Example A instead of methyl6-aminonicotinate, 650 mg (yield 25%) of the target compound wasobtained.

¹H-NMR (DMSO-d₆) δ9.74 (1H, s), 8.52 (1H, s), 8.19 (1H, d, J=9.2 Hz),7.84 (1H, d, J=9.6 Hz), 7.67 (1H, d, J=8.8 Hz), 7.30 (1H, d, J=2.4 Hz),7.11 (1H, dd, J=8.8, 2.4 Hz), 5.41 (1H, s), 4.50 (2H, s), 3.80 (2H, t,J=5.2 Hz), 2.89 (2H, t, J=5.2 Hz), 1.51 (6H, s); LRMS (ESI) m/z 422[M+H]⁺.

Example 74-(4-((5-(2-Hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thesolid (50 mg) obtained from Reference Example 1-2 and the solid (25 mg)obtained from Reference Example 3 instead of methyl 6-aminonicotinate,17 mg (26%) of the target compound was obtained.

¹H-NMR (DMSO-d₆) δ9.04 (1H, s), 8.53 (1H, s), 8.41 (1H, d, J=2.4 Hz),8.02 (1H, d, J=8.5 Hz), 7.86 (1H, d, J=8.8 Hz), 7.82 (1H, dd, J=8.5, 2.4Hz), 7.43 (1H, d, J=2.4 Hz), 7.37 (1H, dd, J=8.8, 2.4 Hz), 5.14 (1H, s),4.54 (2H, s), 3.85 (2H, t, J=5.6 Hz), 2.86 (2H, t, 5.4 Hz), 1.45 (6H,s); LRMS (ESI) m/z 455 [M+H]⁺.

Example 84-(4-((5-(2-Hydroxypropan-2-yl)-4-(trifluoromethyl)thiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of2-((tert-butoxycarbonyl)amino)-4-(trifluoromethyl)thiazol-5-carboxylicacid ethyl ester

2-Amino-4-(trifluoromethyl)thiazol-5-carboxylic acid ethyl ester (1.0 g)was dissolved in THF and added with Boc₂O (1.0 g) and DMAP (25 mg),followed by stirring at 60° C. for 1 hour. The reaction solution wasconcentrated and dried and then purified by silica gel columnchromatography to obtain the target compound (1.14 g, 80%).

¹H-NMR (CDCl₃) δ8.63 (1H, br-s), 4.36 (2H, q, J=7.1 Hz), 1.55 (9H, s),1.36 (3H, t, J=7.1 Hz); LRMS (ESI) m/z 285 [M-tert-butyl+H]⁺.

Step 2 Synthesis of tert-butyl(5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)thiazol-2-yl)carbamate

The compound (450 mg) obtained from step 1 was dissolved in THF andadded dropwise with methyl lithium (3.0 mol/L diethoxymethane solution;1.76 mL) at −78° C. under argon gas atmosphere, followed by stirring for40 minutes. The reaction solution was added dropwise with a saturatedaqueous solution of ammonium chloride and extracted with ethyl acetateand washed with saturated brine. It was dried over sodium sulfate andconcentrated, and then purified by silica gel column chromatography toobtain the target compound (410 mg, 95%).

¹H-NMR (CDCl₃) δ8.05 (1H, br-s), 2.36 (1H, s), 1.71 (6H, s), 1.51 (9H,s); LRMS (ESI) m/z 271 [M-tert-butyl+H]⁺.

Step 3 Synthesis of2-(2-amino-4-(trifluoromethyl)thiazol-5-yl)propan-2-ol

The compound (250 mg) obtained from step 2 was dissolved in methylenechloride (5 mL) and added with TFA (1 mL), followed by stirring at 0° C.for 60 hours and at room temperature for 7 hours. A saturated aqueoussolution of sodium bicarbonate was added dropwise thereto, followed byextraction with ethyl acetate. After drying over sodium sulfate andconcentration, it was purified by silica gel column chromatography toobtain the target compound (50 mg, 29%).

¹H-NMR (CDCl₃) δ4.89 (2H, br-s), 2.31 (1H, s), 1.68 (6H, s); LRMS (ESI)m/z 227 [M+H]⁺.

Step 4 Synthesis of4-(4-((5-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)thiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thecompound (37 mg) obtained from step 3 instead of methyl6-aminonicotinate and performing the reaction at 150° C. for 25 minutesunder irradiation of microwave instead of overnight stirring at 80° C.,the target compound was obtained (48 mg, 62%).

¹H-NMR (DMSO-d₆) δ11.29 (1H, s), 8.73 (1H, s), 7.87 (1H, d, J=8.8 Hz),7.46 (1H, d, J=2.4 Hz), 7.38 (1H, dd, J=2.4, 8.8 Hz), 6.14 (1H, s), 4.59(2H, s), 3.86 (2H, t, J=5.2 Hz), 2.92 (2H, t, J=5.2 Hz), 1.58 (6H, s);LRMS (ESI) m/z 529 [M+H]⁺.

Example 9

2-Chloro-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thecompound (3.0 g) obtained from Reference Example 1-3 instead of thecompound obtained from Reference Example 1-2 and the compound (1.59 g)obtained from Reference Example 3 instead of methyl 6-aminonicotinate,the target compound was obtained (1.0 g, 23%).

¹H-NMR (DMSO-d₆) δ9.04 (1H, s), 8.53 (1H, s), 8.42 (1H, d, J=2.6 Hz),8.03 (1H, d, J=8.8 Hz), 7.83 (1H, dd, J=2.6, 8.8 Hz), 7.69 (1H, d, J=8.8Hz), 7.31 (1H, d, J=2.6 Hz), 7.11 (1H, dd, J=2.6, 8.8 Hz), 5.14 (1H, s),4.48 (2H, s), 3.80 (2H, t, J=5.7 Hz), 2.85 (2H, t, J=5.7 Hz), 1.46 (6H,s); LRMS (ESI) m/z 421 [M+H]⁺.

Example 104-(4-((6-(2-Hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thecompound (30 mg) obtained from Production Example A instead of methyl6-aminonicotinate and performing the reaction at 150° C. for 25 minutesunder irradiation of microwave instead of overnight stirring at 80° C.,the target compound was obtained (30 mg, 36%).

¹H-NMR (DMSO-d₆) δ9.74 (1H, s), 8.52 (1H, s), 8.19 (1H, d, J=9.2 Hz),7.88-7.81 (1H, m), 7.43 (1H, d, J=2.2 Hz), 7.37 (1H, dd, J=2.2, 8.8 Hz),5.40 (1H, s), 4.56 (2H, s), 3.87 (2H, t, J=5.7 Hz), 2.91 (2H, t, J=5.7Hz), 1.51 (6H, s); LRMS (ESI) m/z 456 [M+H]⁺.

Example 116-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8,-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide

The compound (8.24 g) obtained from Reference Example 2-2 and DMT-MM(10.36 g) were suspended in methanol (20 mL) and N,N-dimethylformamide(40 mL), and added with 2,2,2-trifluoroethylamine (3.71 g), followed bystirring overnight at room temperature. The reaction solution was addedwith distilled water and extracted three times with ethyl acetate. Theorganic layer was collected together, washed with distilled water andsaturated brine, and dried over anhydrous sodium sulfate. The insolublematters were separated by filtration, and the filtrate was concentratedand dried. The obtained solid was purified by silica gel columnchromatography to obtain 6.80 g (70%) of the target compound.

¹H-NMR (DMSO-d₆) δ9.53 (1H, s), 9.13 (1H, t, J=6.2 Hz), 8.84-8.81 (1H,m), 8.64 (1H, s), 8.27-8.20 (1H, m), 7.85 (1H, d, J=8.8 Hz), 7.43 (1H,d, J=2.6 Hz), 7.36 (1H, dd, J=9.0, 2.4 Hz), 4.57 (2H, s), 4.15-4.04 (2H,m), 3.84 (2H, t, J=6.0 Hz), 2.91 (2H, t, 5.2 Hz); LRMS (ESI) m/z 522[M+H]⁺.

Example 124-(4-((5-(1-Hydroxycyclopropyl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of 1-(6-chloropyridin-3-yl)cyclopropanol

Methyl 6-chloronicotinamide (1 g) was suspended in diethyl ether (20mL), and added with titanium tetraisopropoxide (1.76 mL) at roomtemperature under nitrogen atmosphere, followed by stirring for 30minutes. The reaction solution was cooled to −78° C., and added withethyl magnesium bromide (3 M, 6.8 mL), followed by stirring for 4 hoursat −78° C. After further stirring overnight at room temperature, thereaction solution was added with water and extracted three times withchloroform. After drying over sodium sulfate followed by concentrationand purification by silica gel column chromatography, the targetcompound was obtained as an oily product (283 mg, 29%).

¹H-NMR (CDCl₃) δ9.33 (1H, d, J=2.6 Hz), 7.69 (1H, dd, J=8.1, 2.6 Hz),7.28 (1H, d, J=8.1 Hz), 0.95 (4H, t, J=7.3 Hz); LRMS (ESI) m/z 170[M+H]⁺.

Step 2 Synthesis of 1-(6-aminopyridin-3-yl)cyclopropanol

The compound (283 mg) obtained from step 1, benzophenone imine (363 mg),Pd₂ (dba)₃ (76 mg), XantPhos (145 mg), and cesium carbonate (761 mg)were dissolved in THF (10 mL) and stirred for 3 days at 60° C. Afterfiltering the reaction solution, the residues were washed with ethylacetate and the filtrate was concentrated under reduced pressure. Theobtained residues were suspended in THF (5 mL), and added with 2 Nhydrochloric acid, followed by stirring at room temperature for 2 hours.The reaction solution was added with a saturated aqueous solution ofsodium hydrogen carbonate and extracted three times with chloroform.After drying over sodium sulfate and concentration, the obtainedresidues were purified by silica gel column chromatography to obtain thetarget compound (98 mg, 39%).

¹H-NMR (CDCl₃) δ8.71 (1H, d, J=2.3 Hz), 8.03 (1H, dd, J=8.6, 2.3 Hz),6.50 (1H, d, J=8.6 Hz), 1.22 (4H, t, J=7.3 Hz); LRMS (ESI) m/z 151[M+H]⁺.

Step 3 Synthesis of4-(4-((5-(1-hydroxycyclopropyl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By reacting the compound (50 mg) obtained from Reference Example 1-2 andthe compound (27 mg) obtained from step 2 according to Reference Example2-1, the target compound was obtained (9.0 mg, 13%).

¹H-NMR (DMSO-d₆) δ9.61 (1H, s), 8.89 (1H, d, J=1.9 Hz), 8.65 (1H, s),8.27 (1H, dd, J=8.8, 1.9 Hz), 8.22 (1H, d, J=9.1 Hz), 7.86 (1H, d, J=9.1Hz), 7.43 (1H, d, J=2.3 Hz), 7.36 (1H, dd, J=8.8, 2.3 Hz), 4.58 (2H, s),3.84 (2H, t, J=5.6 Hz), 2.91 (2H, t, J=5.6 Hz), 1.07 (4H, t, J=7.3 Hz);LRMS (ESI) m/z 453 [M+H]⁺.

Example 134-(4-((6-Isopropoxypyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using6-isopropoxypyridin-3-amine (54 mg) instead of methyl 6-aminonicotinate,43 mg (32%) of the target compound was obtained.

¹H-NMR (DMSO-d₆) δ8.64 (1H, s), 8.35 (1H, s), 8.28 (1H, d, J=2.9 Hz),7.85 (2H, m), 7.43 (1H, d, J=2.6 Hz), 7.36 (1H, dd, J=8.8, 2.6 Hz), 6.72(1H, d, J=8.8 Hz), 5.18 (1H, quin, J=6.1 Hz), 4.49 (2H, s), 3.88 (2H, t,J=5.7 Hz), 2.76 (2H, t, 5.5 Hz), 1.26 (6H, d, J=6.2 Hz); LRMS (ESI) m/z455 [M+H]⁺.

Example 144-(4-((4-(2-(1-Methyl-1H-pyrazol-5-yl)ethoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of 2-(1-methyl-1H-pyrazol-5-yl)ethanol

1-Methyl-1H-pyrazole (3.57 g) was dissolved in THF (50 mL), and addedwith tert-butyllithium (30.5 mL, 1.6 mol/L pentane solution) at −78° C.,followed by stirring under nitrogen atmosphere at −60° C. for 30 minutesand at −10° C. for 40 minutes. The reaction solution was added dropwisewith a THF solution (50 mL) of oxirane (2.42 g) at −10° C. The reactionsolution was stirred overnight at room temperature, and added with asaturated aqueous solution of ammonium chloride, followed by extractionthree times with chloroform. The organic layer was dried over sodiumsulfate, followed by concentration and purification by silica gel columnchromatography to obtain the target compound (2.42 g, 45%).

¹H-NMR (DMSO-d₆) δ7.24 (1H, d, J=1.8 Hz), 6.02 (1H, d, J=1.8 Hz), 4.76(1H, t, J=5.3 Hz), 3.71 (3H, s), 3.60 (2H, td, J=6.9, 5.3 Hz), 2.74 (2H,t, J=6.9 Hz); LRMS (ESI) m/z 127 [M+H]⁺.

Step 2 Synthesis of4-(4-((4-(benzyloxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using4-(benzyloxy)aniline (706 mg) instead of methyl 6-aminonicotinate, thetarget compound was obtained (1.39 g, 94%).

¹H-NMR (MeOH-d₄) δ8.30 (1H, s), 7.76 (1H, d, J=9.0 Hz), 7.47-7.24 (9H,m), 7.02-6.97 (2H, m), 5.09 (2H, s), 4.45 (2H, s), 3.89 (2H, t, J=5.8Hz), 2.80 (2H, t, J=5.8 Hz); LRMS (ESI) m/z 502 [M+H]⁺.

Step 3 Synthesis of4-(4-((4-hydroxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (1.39 g) obtained from step 2, 10% palladium/carbon(containing 50% water, 300 mg), and ammonium formate (872 mg) weresuspended in methanol (30 mL) and stirred overnight at 60° C. Thereaction solution was filtered and the residues were washed withchloroform-methanol. Water was added thereto, followed by extractionfour times with chloroform-methanol (3:1). After drying over sodiumsulfate followed by concentration, the target compound was obtained (971mg, 85%).

¹H-NMR (DMSO-d₆) δ9.25 (1H, br-s), 8.43 (1H, s), 8.33 (1H, s), 7.87 (1H,d, J=8.8 Hz), 7.46-7.30 (4H, m), 6.73 (1H, d, J=8.3 Hz), 4.48 (2H, s),3.88 (2H, t, J=5.6 Hz), 2.75 (2H, t, J=5.6 Hz); LRMS (ESI) m/z 412[M+H]⁺.

Step 4 Synthesis of4-(4-((4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (802 mg) obtained from step 3,cyanomethylenetributylphosphrane (Tsunoda Reagent, 565 mg), and2-(1-methyl-1H-pyrazol-5-yl)ethanol (246 mg) obtained from step 1 weredissolved in toluene (10 mL)-tetrahydrofuran (8 mL), and stirredovernight at 95° C. The solvent was concentrated and purification bysilica gel column chromatography was performed to obtain the targetcompound (724 mg, 71%).

¹H-NMR (CDCl₃) δ8.55 (1H, s), 7.69 (1H, d, J=8.8 Hz), 7.47-7.39 (3H, m),7.24 (1H, d, J=2.4 Hz), 7.06 (1H, dd, J=8.8, 2.4 Hz), 6.96-6.90 (2H, m),6.32 (1H, br-s), 6.14 (1H, d, J=1.5 Hz), 4.49 (2H, s), 4.22 (2H, t,J=6.6 Hz), 3.89 (3H, s), 3.87 (2H, t, J=5.6 Hz), 3.13 (2H, t, J=6.6 Hz),2.76 (2H, t, J=5.6 Hz); LRMS (ESI) m/z 520 [M+H]⁺.

Example 154-(4-((6-(2-(1H-1,2,3-Triazol-1-yl)ethoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of 2-(2-(1H-1,2,3-triazol-1-yl)ethoxy)-5-nitropyridine

2-Chloro-5-nitropyridine (300 mg) was dissolved in THF, and added withsodium hydride (151 mg, 60%) at 0° C., followed by stirring for 10minutes. After further added with 2-(1H-1,2,3-triazol-1-yl)ethanol, itwas stirred for 2 hours at 0° C. The reaction solution was added withwater and extracted with ethyl acetate three times. The organic layerwas washed with water and saturated brine, followed by drying oversodium sulfate and concentration. The obtained residues were purified bysilica gel column chromatography to obtain the target compound (376 mg,90%).

¹H-NMR (DMSO-d₆) δ9.05 (1H, d, J=2.9 Hz), 8.47 (1H, dd, J=9.2, 2.9 Hz),8.20 (1H, s), 7.73 (1H, s), 7.07 (1H, d, J=9.2 Hz), 4.87-4.78 (4H, m);LRMS (ESI) m/z 236 [M+H]⁺.

Step 2 Synthesis of 6-(2-(1H-1,2,3-triazol-1-yl)ethoxy)pyridin-3-amine

The compound (270 mg) obtained from step 1 was dissolved in methanol (8mL) and added with 10% palladium/carbon (135 mg, containing 50% water).Under hydrogen atmosphere, it was stirred overnight at atmosphericpressure. The reaction solution was filtered through Hyflo Super-Cel,and the solvent was concentrated to obtain the target compound as acolorless oily product (200 mg).

¹H-NMR (DMSO-d₆) δ8.11 (1H, d, J=1.0 Hz), 7.70 (1H, d, J=1.0 Hz), 7.46(1H, d, J=2.9 Hz), 6.97 (1H, dd, J=8.4, 2.9 Hz), 6.49 (1H, d, J=8.4 Hz),4.77 (2H, s), 4.70 (2H, t, J=5.3 Hz), 4.48 (2H, t, J=5.3 Hz); LRMS (ESI)m/z 206 [M+H]⁺.

Step 3 Synthesis of4-(4-((6-(2-(1H-1,2,3-triazol-1-yl)ethoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By reacting the compound (50 mg) obtained from Reference Example 1-2 andthe compound (36 mg) obtained from step 2 according to Reference Example2-1, the target compound was obtained (28 mg, 37%).

¹H-NMR (DMSO-d₆) δ8.69 (1H, s), 8.38 (1H, s), 8.33 (1H, d, J=2.6 Hz),8.19 (1H, s), 7.92 (1H, dd, J=8.8, 2.6 Hz), 7.87 (1H, d, J=8.8 Hz), 7.73(1H, s), 7.44 (1H, d, J=2.2 Hz), 7.38 (1H, dd, J=8.8, 2.2 Hz), 6.79 (1H,d, J=8.8 Hz), 4.79 (2H, t, J=5.2 Hz), 4.65 (2H, t, J=5.2 Hz), 4.51 (2H,s), 3.89 (2H, t, J=5.6 Hz), 2.78 (2H, t, J=5.6 Hz); LRMS (ESI) m/z 508[M+H]⁺.

Example 164-(4-((6-(2-Methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of 2-methyl-2-(1H-tetrazol-1-yl)propan-1-ol

2-Amino-2-methylpropan-1-ol (30 g), triethyl orthoformate (64.8 g), andsodium azide (26.3 g) were suspended in acetic acid (150 mL) and stirredovernight at reflux conditions. The reaction solution was added withconc. hydrochloric acid (40 mL) and the produced insoluble matters wereremoved by filtration. The filtrate was concentrated under reducedpressure to remove the solvent, and the obtained residues were purifiedby silica gel column chromatography to obtain a solid. The obtainedsolid was suspended in toluene, and after filtering and washing withtoluene, it was dried under reduced pressure to obtain the targetcompound (28.5 g, 60%).

¹H-NMR (DMSO-d₆) δ9.39 (1H, s), 5.24 (1H, t, J=5.6 Hz), 3.59 (2H, d,J=5.6 Hz), 1.56 (6H, s); LRMS (ESI) m/z 143 [M+H]⁺.

Step 2 Synthesis of6-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-amine

By performing the same operation as step 1 and step 2 of Example 15 andusing 2-methyl-2-(1H-tetrazol-1-yl)propan-1-ol (2.82 g) obtained fromstep 1 instead of 2-(1H-1,2,3-triazol-1-yl)ethanol, the target compoundwas obtained (3.84 g, two step yield 86%).

¹H-NMR (DMSO-d₆) δ9.54 (1H, s), 7.42 (1H, d, J=2.9 Hz), 6.96 (1H, dd,J=8.8, 2.9 Hz), 6.46 (1H, d, J=8.8 Hz), 4.79 (2H, br-s), 4.40 (2H, s),1.72 (6H, s); LRMS (ESI) m/z 235 [M+H]⁺.

Step 3 Synthesis of4-(4-((6-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By reacting the compound (2.0 g) obtained from Reference Example 1-2 andthe compound (1.52 g) obtained from step 2 according to ReferenceExample 2-1, the target compound was obtained (1.49 g, 47%).

¹H-NMR (DMSO-d₆) δ9.60 (1H, s), 8.68 (1H, s), 8.39 (1H, s), 8.27 (1H, d,J=2.7 Hz), 7.92 (1H, dd, J=8.8, 2.7 Hz), 7.87 (1H, d, J=8.8 Hz), 7.44(1H, d, J=2.5 Hz), 7.38 (1H, dd, J=9.1, 2.5 Hz), 6.75 (1H, d, J=9.1Hz)), 4.57 (2H, s), 4.50 (2H, br-s) 3.89 (2H, t, J=5.6 Hz), 2.77 (2H, t,J=5.6 Hz) 1.76 (6H, s); LRMS (ESI) m/z 537 [M+H]⁺.

Example 174-(4-((5-(2-Methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of2-bromo-5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridine

2-Methyl-2-(1H-tetrazol-1-yl)propan-1-ol (3.27 g) obtained from step 1of Example 16, 6-bromopyridin-3-ol (4.00 g), andcyanomethylenetributylphosphrane (Tsunoda Reagent, 9.99 g) weredissolved in toluene (100 mL) and stirred overnight under reflux. Thesolvent was concentrated and purification by silica gel columnchromatography was performed to obtain the target compound (5.08 g,74%).

¹H-NMR (DMSO-d₆) δ9.60 (1H, s), 8.08 (1H, d, J=3.3 Hz), 7.53 (1H, d,J=8.8 Hz), 7.36 (1H, dd, J=8.8, 3.3 Hz), 4.39 (2H, s), 1.76 (6H, s);LRMS (ESI) m/z 298 [M+H]⁺.

Step 2 Synthesis of tert-butyl(5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-yl)carbamate

The compound (4 g) obtained from step 1, tert-butylcarbamate (4.72 g),Pd₂ (dba)₃ (1.23 g), XantPhos (2.33 g) and sodium tert-butoxide (2.58 g)were dissolved in dioxane (100 mL) and stirred overnight under reflux.The reaction solution was added with water and extracted three timeswith chloroform. After drying over sodium sulfate and concentration, theobtained residues were purified by silica gel column chromatography toobtain the target compound (3.36 g, 74%).

¹H-NMR (DMSO-d₆) δ9.59 (1H, s), 9.58 (1H, br-s), 7.89 (1H, d, J=3.0 Hz),7.66 (1H, d, J=9.1 Hz), 7.33 (1H, dd, J=9.1, 3.0 Hz), 4.32 (2H, s), 1.75(6H, s), 1.44 (9H, s); LRMS (ESI) m/z 335 [M+H]⁺.

Step 3 Synthesis of5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-amine

The compound (185 mg) obtained from step 2 was dissolved in 4 Nhydrochloric acid-dioxane solution (3 mL) and stirred overnight underreflux. The reaction solution was added with a saturated aqueoussolution of sodium hydrogen carbonate and extracted three times withchloroform. After drying over sodium sulfate and concentration, thetarget compound was obtained as a yellow oily product (130 mg, 100%).

¹H-NMR (DMSO-d₆) δ9.60 (1H, s), 7.56 (1H, d, J=3.0 Hz), 7.01 (1H, dd,J=8.9, 3.0 Hz), 6.36 (1H, d, J=8.9 Hz), 5.52 (2H, br-s), 4.18 (2H, s),1.76 (6H, s); LRMS (ESI) m/z 235 [M+H]⁺.

Step 4 Synthesis of4-(4-((5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By reacting the compound (1.6 g) obtained from Reference Example 1-2 andthe compound (1.14 g) obtained from step 3 according to ReferenceExample 2-1, the target compound was obtained (0.80 g, 32%).

¹H-NMR (DMSO-d₆) δ9.62 (1H, s), 9.02 (1H, s), 8.49 (1H, s), 8.01 (1H, d,J=3.1 Hz), 7.99 (1H, d, J=9.1 Hz), 7.86 (1H, d, J=8.8 Hz), 7.46-7.34(3H, m), 4.53 (2H, br-s), 4.37 (2H, s), 3.85 (2H, t, J=5.7 Hz), 2.84(2H, t, J=5.7 Hz) 1.77 (6H, s); LRMS (ESI) m/z 537 [M+H]⁺.

Example 184-(4-((4-(3-(4-(Methylsulfonyl)piperazin-1-yl)propoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of tert-butyl4-(3-(4-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)propyl)piperazin-1-carboxylate

By performing the same operation as Example 14 (step 4) and usingtert-butyl 4-(3-hydroxypropyl)piperazin-1-carboxylate (65 mg) instead of2-(1-methyl-1H-pyrazol-5-yl)ethanol, the target compound was obtained(140 mg, 92%).

¹H-NMR (CDCl₃) δ8.61 (1H, s), 7.69 (1H, d, J=8.8 Hz), 7.34-7.31 (1H, m),7.29-7.22 (2H, m), 7.06 (2H, dd, J=8.8, 2.7 Hz), 6.70 (1H, d, J=8.3, 2.2Hz), 6.50 (1H, s), 4.49 (2H, s), 4.05 (2H, t, J=6.2 Hz), 3.87 (2H, t,J=5.6 Hz), 3.48-3.38 (4H, m), 2.79 (2H, t, J=5.6 Hz), 2.54 (2H, t, J=7.2Hz), 2.46-2.35 (4H, m), 2.04-1.92 (2H, m); LRMS (ESI) m/z 638 [M+H]⁺.

Step 2 Synthesis of4-(4-((4-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (140 mg) obtained from step 1 was added with 10%hydrochloric acid-methanol solution, followed by stirring for 3 hours at50° C. The solvent was concentrated to obtain a de-Boc product (132 mg).A part (30 mg) of the obtained solid was suspended in dichloromethane,and added sequentially with triethylamine (22 μL) and methanesulfonylchloride (5 μL), followed by stirring for 2 hours at room temperature.The reaction solution was added with water and extracted three timeswith chloroform. After drying over sodium sulfate and concentration,purification by silica gel column chromatography was performed to obtainthe target compound (6.7 mg, 21%).

¹H-NMR (CDCl₃) δ8.54 (1H, s), 7.68 (1H, d, J=8.8 Hz), 7.45-7.36 (2H, m),7.23 (1H, d, J=2.7 Hz), 7.06 (1H, dd, J=8.8, 2.7 Hz), 6.95-6.89 (2H, m),6.32 (1H, s), 4.48 (2H, s), 4.03 (2H, t, J=6.1 Hz), 3.87 (2H, t, J=5.7Hz), 3.72 (1H, q, J=7.0 Hz), 3.30-3.23 (4H, m), 2.83-2.73 (2H, m), 2.78(3H, s), 2.63-2.55 (5H, m) 2.02-1.93 (2H, m); LRMS (ESI) m/z 616 [M+H]⁺.

Example 196-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-cyclopropylpyridine-3-sulfonamide

Step 1 Synthesis of 6-chloro-N-cyclopropylpyridine-3-sulfonamide

6-Chloropyridine-3-sulfonyl chloride (300 mg) and triethylamine (0.59mL) were dissolved in dichloromethane (6 mL), and added withcyclopropylamine (121 mg) and dimethylaminopyridine (5 mg), followed bystirring overnight at room temperature. The reaction solution was addedwith water and extracted three times with chloroform. After drying oversodium sulfate and concentration, the target compound was obtained (442mg).

¹H-NMR (DMSO-d₆) δ8.78 (1H, d, J=2.6 Hz), 8.24 (1H, br-s), 8.20 (1H, dd,J=8.4, 2.6 Hz), 7.81 (1, d, J=8.4 Hz), 2.25-2.17 (1H, m), 0.56-0.49 (2H,m), 0.40-0.36 (2H, m); LRMS (ESI) m/z 233 [M+H]⁺.

Step 2 Synthesis of 6-amino-N-cyclopropylpyridine-3-sulfonamide

The compound (200 mg) obtained from step 1 was dissolved in ethanol (2mL) and added with 28% ammonia water (2 mL), followed by stirring for 1hour at 140° C. under irradiation of microwave. After concentrating thereaction solution, the obtained residues were purified by silica gelcolumn chromatography to obtain the target compound (90 mg, two stepyield 66%).

¹H-NMR (CDCl₃) δ8.27 (1H, d, J=2.2 Hz), 7.65 (1H, dd, J=8.8, 2.6 Hz),7.60 (1H, d, J=2.6 Hz), 6.87 (2H, s), 6.52 (1H, d, J=8.8 Hz), 2.13-2.05(1H, m), 0.52-0.45 (2H, m), 0.39-0.33 (2H, m); LRMS (ESI) m/z 214[M+H]⁺.

Step 3 Synthesis of6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-cyclopropylpyridine-3-sulfonamide

By reacting the compound (50 mg) obtained from Reference Example 1-2 andthe compound (38 mg) obtained from step 2 according to Reference Example2-1, the target compound was obtained (21 mg, 28%).

¹H-NMR (DMSO-d₆) δ9.74 (1H, s), 8.68 (1H, s), 8.67 (1H, dd, J=2.6, 0.8Hz), 8.33 (1H, dd, J=8.8, 0.8 Hz), 8.12 (1H, dd, J=8.8, 2.6 Hz), 7.95(1H, d, J=2.8 Hz), 7.88 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=2.2 Hz), 7.39(1H, dd, J=8.8, 2.8 Hz), 4.61 (2H, s), 3.86 (2H, t, J=5.8 Hz), 2.94 (2H,t, J=5.8 Hz), 2.24-2.15 (1H, m), 0.57-0.49 (2H, m), 0.43-0.36 (2H, m);LRMS (ESI) m/z 516 [M+H]⁺.

Example 204-(4-((5-((1,4-Oxazepan-4-yl)sulfonyl)thiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis ofN-(5-((1,4-oxazepan-4-yl)sulfonyl)thiazol-2-yl)acetamide

2-(Acetylamino)-1,3-thiazol-5-sulfonyl chloride (200 mg) was dissolvedin DMF (5 mL) and added with 1,4-oxazepane hydrochloride (170 mg) andDIPEA (424 μL), followed by stirring for 6 hours at room temperature.The reaction solution was added with an aqueous solution of ammoniumchloride, and the precipitates were collected by filtration to obtainthe target compound (200 mg, 79%).

¹H-NMR (DMSO-d₆) δ13.03 (1H, br-s), 8.31 (1H, s), 3.99-3.95 (4H, m),3.71-3.58 (4H, m), 2.52 (3H, s), 2.16-2.10 (2H, m); LRMS (ESI) m/z 306[M+H]⁺.

Step 2 Synthesis of 5-((1,4-oxazepan-4-yl)sulfonyl)thiazol-2-amine

The compound (183 mg) obtained from step 1 was dissolved in ethanol (4mL) and added with 4.0 mol/L hydrochloric acid (dioxane solution, 1.2mL), followed by stirring for 4.5 hours at 70° C. After concentratingthe reaction solution, ammonia water was added under ice cooling and theprecipitates were collected by filtration to obtain the target compound(110 mg, 70%).

¹H-NMR (DMSO-d₆) δ7.88 (2H, br-s), 7.45 (1H, s), 3.67-3.64 (4H, m),3.39-3.27 (4H, m), 1.84-1.78 (2H, m); LRMS (ESI) m/z 264 [M+H]⁺.

Step 3 Synthesis of4-(4-((5-((1,4-oxazepan-4-yl)sulfonyl)thiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thecompound (47 mg) obtained from step 2 instead of methyl6-aminonicotinate and carrying out the reaction for 30 minutes at 150°C. under microwave irradiation instead of stirring overnight at 80° C.,the target compound was obtained (10 mg, 12%).

¹H-NMR (DMSO-d₆) δ11.97 (1H, br-s), 8.81 (1H, s), 8.03 (1H, s), 7.87(1H, d, J=8.8 Hz), 7.45 (1H, d, 2.0 Hz), 7.38 (1H, dd, J=2.0, 8.8 Hz),4.61 (2H, s), 3.86 (2H, t, 5.6 Hz), 3.69-3.63 (4H, m), 3.42-3.30 (4H,m), 2.94 (2H, t, 5.6 Hz), 1.84-1.78 (2H, m); LRMS (ESI) m/z 566 [M+H]⁺.

Example 21 2,2,2-Trifluoroethyl(6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8,-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)carbamate

The compound (100 mg) obtained from Reference Example 2-2,diphenylphosphoryl azide (188 mg), 2,2,2-trifluoroethanol (68 mg), andN,N-diisopropylethylamine (88 mg) were suspended in dioxane (2.5 mL) andstirred for 2 hours at 125° C. under microwave irradiation. The obtainedreaction solution was concentrated and dried, and purification by silicagel column chromatography was performed to obtain the target compound5.8 mg (2.4%).

¹H-NMR (DMSO-d₆) δ10.24 (1H, s), 9.08 (1H, s), 8.51 (1H, s), 8.42 (1H,s), 8.07 (1H, d, J=9.2 Hz), 7.89-7.82 (2H, m), 7.43 (1H, d, J=1.8 Hz),7.36 (1H, dd, J=8.8, 2.6 Hz), 4.79 (2H, q, J=9.2 Hz), 4.53 (2H, s), 3.84(2H, t, J=5.9 Hz), 2.85 (2H, t, 5.1 Hz); LRMS (ESI) m/z 538 [M+H]⁺.

Example 222-(6-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)acetamide

Step 1 Synthesis of2-(6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)aceticacid

By performing the same operation as Reference Examples 2-1 and 2-2 andusing ethyl 2-(6-aminopyridin-3-yl)acetate (175 mg) instead of methyl6-aminonicotinate, the target compound was obtained (94 mg, two stepyield 26%).

¹H-NMR (DMSO-d₆) δ9.73 (1H, br-s), 8.64 (1H, s), 8.27 (1H, d, J=1.1 Hz),8.03 (1H, d, J=8.8 Hz), 7.89 (1H, d, J=8.8 Hz), 7.84 (1H, dd, J=8.8, 1.1Hz), 7.45 (1H, d, J=2.1 Hz), 7.39 (1H, dd, J=8.8, 2.1 Hz), 4.60 (2H, s),3.88 (2H, t, J=5.2 Hz), 3.66 (2H, s), 2.91 (2H, t, J=5.2 Hz); LRMS (ESI)m/z 455 [M+H]⁺.

Step 2 Synthesis of2-(6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)acetamide

By performing the same operation as Example 11 and using the compound(30 mg) obtained from step 1 instead of the compound obtained fromReference Example 2-2, the target compound was obtained (29 mg, 83%).

¹H-NMR (DMSO-d₆) δ9.10 (1H, br-s), 8.79 (1H, t, J=6.2 Hz), 8.54 (1H, s),8.20 (1H, d, J=2.2 Hz), 8.07 (1H, d, J=8.4 Hz), 7.87 (1H, d, J=8.8 Hz),7.66 (1H, dd, J=8.4, 2.4 Hz), 7.44 (1H, d, J=2.2 Hz), 7.37 (1H, dd,J=8.8, 2.4 Hz), 4.55 (2H, s), 3.98-3.82 (4H, m), 3.52 (2H, s), 2.88 (2H,t, J=5.5 Hz); LRMS (ESI) m/z 536 [M+H]⁺.

Example 23N-(6-((7-(4-Cano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)-3,3,3-trifluoropropanamide

Step 14-(4-((5-Nitropyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Reference Example 2-1 and using5-nitropyridin-2-amine (986 mg) instead of methyl 6-aminonicotinate, thetarget compound was obtained (810 mg, 31%).

¹H-NMR (DMSO-d₆) δ10.11 (1H, s), 9.14 (1H, d, J=2.9 Hz), 8.71 (1H, s),8.54 (1H, dd, J=9.3, 2.7 Hz), 8.27 (1H, d, J=9.5 Hz), 7.86 (1H, d, J=8.8Hz), 7.43 (1H, d, J=2.2 Hz), 7.37 (1H, dd, J=8.8, 2.6 Hz), 4.61 (2H, s),3.84 (2H, t, J=5.7 Hz), 2.94 (2H, t, 5.7 Hz); LRMS (ESI) m/z 442 [M+H]⁺.

Step 24-(4-((5-Aminopyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (100 mg) obtained from step 1 and 10% palladium/carbon (10mg) were suspended in methanol (2.0 mL) and stirred for 2 days at roomtemperature under hydrogen atmosphere. The obtained suspension wasfiltered through Celite, and the filtrate was concentrated and dried toobtain 12 mg (13%) of the target compound.

¹H-NMR (DMSO-d₆) δ8.67 (1H, s), 8.40 (1H, s), 7.86 (1H, d, J=8.8 Hz),7.72 (1H, d, J=2.9 Hz), 7.67 (1H, d, J=8.8 Hz), 7.43 (1H, d, J=2.6 Hz),7.36 (1H, dd, J=8.8, 2.6 Hz), 7.00 (1H, dd, J=8.6, 2.7 Hz), 5.12 (2H,s), 4.49 (2H, s), 3.85 (2H, t, J=5.9 Hz), 2.78 (2H, t, 5.5 Hz); LRMS(ESI) m/z 412 [M+H]⁺.

Step 3N-(6-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)-3,3,3-trifluoropropanamide

By performing the same operation as Example 11 and using3,3,3-trifluoropropanoic acid (7.0 mg) instead of6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinicacid and the compound (15 mg) obtained from step 3 instead of2,2,2-trifluoroethylamine, 2.8 mg (15%) of the target compound wasobtained.

¹H-NMR (DMSO-d₆) δ10.51 (1H, s), 9.14 (1H, s), 8.57 (1H, d, J=2.6 Hz),8.53 (1H, s), 8.12 (1H, d, J=8.8 Hz), 7.91 (1H, dd, J=8.8, 2.6 Hz), 7.86(1H, d, J=8.8 Hz), 7.43 (1H, d, J=2.6 Hz), 7.37 (1H, dd, J=9.0, 2.4 Hz),4.54 (2H, s), 3.85 (2H, t, J=5.8 Hz), 3.53 (2H, q, J=11.2 Hz), 2.86 (2H,t, 5.5 Hz); LRMS (ESI) m/z 522 [M+H]⁺.

Example 246-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide

By performing the same operation as Example 11 and using the compound(5.0 mg) obtained from Production Example B instead of the compoundobtained from Reference Example 2-2 and HATU (8.6 mg) and DIPEA (8.1 μL)instead of DMT-MM, the target compound was obtained (1.22 mg) (yield21%).

¹H-NMR (DMSO-d₆) δ9.53 (1H, t, J=6.5 Hz), 8.62 (1H, s), 8.49-8.42 (2H,m), 8.15 (1H, d, J=9.6 Hz), 7.85 (1H, d, J=8.9 Hz), 7.45 (1H, s), 7.36(1H, d, J=8.9 Hz), 4.59 (2H, s), 4.09 (2H, m), 3.85 (2H, t, J=5.5 Hz),2.96 (2H, m) LRMS (ESI) m/z 523 [M+H]⁺.

Example 253-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)-1,2,4-triazine-6-carboxamide

Step 1 Synthesis of 6-bromo-1,2,4-triazine-3-amine

1,2,4-Triazin-3-amine (5.00 g) was dissolved in acetonitrile (45 mL) anddistilled water (75 mL), and under light blocking conditions,N-bromosuccinimide (10.0 g) was added under ice cooling, followed bystirring overnight at room temperature under light blocking conditions.The obtained reaction solution was added with distilled water (100 mL)and extracted three times with ethyl acetate (150 mL). The obtainedorganic layer was combined, and after washing with saturated brine,dried over anhydrous sodium sulfate. The insoluble matters wereseparated by filtration, and the filtrate was concentrated and dried toobtain 2.64 g (yield 29%) of the target compound.

¹H-NMR (DMSO-d₆) δ8.38 (1H, s), 7.45 (2H, br-s); LRMS (ESI) m/z 175[M+H]⁺.

Step 2 Synthesis of methyl 3-amino-1,2,4-triazine-6-carboxylate

By performing the same operation as Example 5 and using the compound(1.0 g) obtained from step 1 of this example instead of the compoundobtained from step 1 of Example 5, 728 mg of the target compound wasobtained (yield 83%).

¹H-NMR (DMSO-d₆) δ8.64 (1H, s), 3.85 (3H, s); LRMS (ESI) m/z 155 [M+H]⁺.

Step 3 Synthesis of3-amino-N-(2,2,2-trifluoroethyl)-1,2,4-triazine-6-carboxamide

The compound (100 mg) obtained from step 2 was dissolved in methanol(6.5 mL), and added with 2 N aqueous solution of sodium hydroxide (4mL), followed by stirring for 3 hours. The reaction solution wasadjusted to have a pH of 4 using 2 N hydrochloric acid, and thenconcentrated and dried under reduced pressure. The obtained residues and2,2,2-trifluoroethylamine (102 μL) were dissolved in a mixed solvent ofDMF (3 mL) and methanol (3 mL), added with DMT-MM, followed by stirringovernight. The reaction solution was added with distilled water andextracted three times with ethyl acetate. The organic layer wascombined, washed with distilled water and saturated brine, and driedover anhydrous sodium sulfate. The insoluble matters were separated byfiltration, and the filtrate was concentrated and dried. Then,purification by silica gel column chromatography was performed to obtainthe target compound (56 mg) (yield 39%).

LRMS (ESI) m/z 222 [M+H]⁺.

Step 4 Synthesis of3-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)-1,2,4-triazine-6-carboxamide

By performing the same operation as Reference Example 2-1 and using thecompound (30 mg) obtained from Reference Example 1-2 and the compound(23 mg) obtained from step 3 instead of methyl 6-aminonicotinate andstirring for 30 minutes at 140° C. under irradiation of microwaveinstead of overnight stirring at 80° C., 32 mg of the target compoundwas obtained (yield 70%).

¹H-NMR (DMSO-d₆) δ9.62 (1H, t, J=6.4 Hz), 8.99 (1H, s), 8.79 (1H, s),8.28 (1H, s), 7.85 (1H, d, J=8.8 Hz), 7.41 (1H, s), 7.36 (1H, dd, J=8.8,2.6 Hz), 4.68 (2H, s), 4.14 (2H, m), 3.79 (2H, m), 2.81 (2H, t, J=5.5Hz); LRMS (ESI) m/z 524 [M+H]⁺.

Example 262-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)thiazol-5-carboxamide

Step 1 Synthesis of ethyl2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-4-(trifluoromethyl)thiazol-5-carboxylate

By performing the same operation as Reference Example 2-1 and usingethyl 2-amino-4-(trifluoromethyl)thiazol-5-carboxylate (341 mg) insteadof methyl 6-aminonicotinate and having the reaction for 30 minutes at150° C. under irradiation of microwave instead of overnight stirring at80° C., the target compound was obtained (670 mg, 100%).

¹H-NMR (DMSO-d₆) δ8.59 (1H, s), 7.79 (1H, d, 8.8 Hz), 7.40 (1H, d, 2.4Hz), 7.33 (1H, dd, J=2.4, 8.8 Hz), 4.43 (2H, s), 4.19 (2H, q, 7.0 Hz),3.79 (2H, t, J=5.9 Hz), 2.80 (2H, t, J=5.9 Hz), 1.25 (3H, t, J=7.0 Hz);LRMS (ESI) m/z 543 [M+H]⁺.

Step 2 Synthesis of2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-4-(trifluoromethyl)thiazol-5-carboxylicacid

The compound (670 mg) obtained from step 1 was suspended in ethanol (10mL), and added with 2.0 mol/L aqueous solution of sodium hydroxide (4.8mL), followed by stirring for 6 hours at 60° C. The reaction solutionwas concentrated, diluted with distilled water, and adjusted to have apH of about 5 by using 2.0 mol/L hydrochloric acid. The precipitateswere collected by filtration to obtain the target compound (275 mg,45%).

LRMS (ESI) m/z 515 [M+H]⁺.

Step 3 Synthesis of2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)thiazol-5-carboxamide

By performing the same operation as Example 11 and using the compound(40 mg) obtained from step 2 instead of the compound obtained fromReference Example 2-2 and HOBt (13 mg) and WSC (16 mg) instead ofDMT-MM, the target compound was obtained (11 mg, 24%).

¹H-NMR (DMSO-d₆) δ12.02 (1H, s), 9.43 (1H, t, J=6.2 Hz), 8.83 (1H, s),7.88 (1H, d, J=8.8 Hz), 7.48 (1H, d, J=2.4 Hz), 7.40 (1H, dd, J=2.4, 8.8Hz), 4.63 (2H, s), 4.11-4.01 (2H, m), 3.88 (2H, t, J=5.7 Hz), 2.96 (2H,t, J=5.7 Hz); LRMS (ESI) m/z 596 [M+H]⁺.

Example 276-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2-difluoroethyl)nicotinamide

By performing the same operation as Example 11 and using2,2-difluoroethylamine instead of 2,2,2-trifluoroethylamine and HATU andDIPEA instead of DMT-MM, the target compound was obtained (yield 58%).

¹H-NMR (DMSO-d₆) δ9.48 (1H, s), 8.90 (1H, t, J=5.8 Hz), 8.80 (1H, s),8.62 (1H, s), 8.25-8.16 (2H, m), 7.84 (1H, d, J=8.9 Hz), 7.42 (1H, s),7.35 (1H, d, J=8.9 Hz), 6.10 (1H, t, J=56 Hz), 4.56 (2H, s), 3.83 (2H,t, J=5.5 Hz), 3.66 (2H, m), 2.90 (2H, m) LRMS (ESI) m/z 504 [M+H]⁺.

Example 286-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2-difluoroethyl)pyridazine-3-carboxamide

By performing the same operation as Example 11 and using the compound(5.0 mg) obtained from Production Example B instead of the compoundobtained from Reference Example 2-2, 2,2-difluoroethylamine instead of2,2,2-trifluoroethylamine, and HATU (8.6 mg) and DIPEA (8.1 μL) insteadof DMT-MM, the target compound was obtained (3.52 mg) (yield 62%).

¹H-NMR (DMSO-d₆) δ10.22 (1H, br-s), 9.26 (1H, t, J=6.2 Hz), 8.62 (1H,s), 8.44 (1H, d, J=9.6 Hz), 8.14 (1H, d, J=8.9 Hz), 7.85 (1H, d, J=8.9Hz), 7.43 (1H, s), 7.36 (1H, d, J=8.9 Hz), 6.14 (1H, t, J=56 Hz), 4.59(2H, s), 3.85 (2H, m), 3.73 (2H, m), 2.96 (2H, m) LRMS (ESI) m/z 505[M+H]⁺.

Example 296-((7-(3-Chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-((1r,4r)-4-hydroxycyclohexyl)pyridazine-3-carboxamide

Step 1 Synthesis of methyl6-((7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridazine-3-carboxylate

By performing the same operation as Reference Example 2-1 and usingmethyl 6-aminopyridazine-3-carboxylate (353 mg) instead of methyl6-aminonicotinate and commercially available7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (500 mg)instead of the compound obtained from Reference Example 1-2, the targetcompound was obtained (267 mg, 37%).

¹H-NMR (DMSO-d₆) δ8.56 (1H, s), 8.52 (1H, d, J=9.5 Hz), 8.17 (1H, d,J=9.5 Hz), 7.37 (1H, s), 7.59-7.32 (5H, m), 3.93 (3H, s), 3.68 (2H, s),3.50 (2H, s), 2.83 (2H, t, J=5.5 Hz), 2.74 (2H, t, J=5.5 Hz); LRMS (ESI)m/z 377 [M+H]⁺.

Step 2 Synthesis of methyl6-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridazine-3-carboxylate

By performing the same operation as Reference Example 1-1 for thecompound (260 mg) obtained from step 1 and using2-chloro-4-fluorobenzonitrile (322 mg) instead of4-fluoro-2-(trifluoromethyl)benzonitrile, the target compound wasobtained (34 mg, 12%).

¹H-NMR (CDCl₃) δ9.01 (1H, d, J=8.8 Hz), 8.70 (1H, s), 8.24 (1H, d, J=8.8Hz), 7.56 (1H, d, J=8.8 Hz), 7.40 (1H, s), 7.07 (1H, d, J=2.4 Hz), 6.94(1H, dd, J=8.8, 2.4 Hz), 4.52 (2H, s), 4.06 (3H, s), 3.87 (2H, t, J=5.2Hz), 3.04 (2H, t, J=5.2 Hz); LRMS (ESI) m/z 422 [M+H]⁺.

Step 3 Synthesis of6-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridazine-3-carboxylicacid

By performing the same operation as Reference Example 2-2 and using thecompound (34 mg) obtained from step 2, the target compound was obtained(27 mg, 82%).

¹H-NMR (DMSO-d₆) δ10.33 (1H, br-s), 8.65 (1H, s), 8.47 (1H, d, J=9.3Hz), 8.16 (1H, d, J=9.3 Hz), 7.70 (1H, d, J=8.8 Hz), 7.33 (1H, d, J=2.4Hz), 7.13 (1H, dd, J=8.8, 2.4 Hz), 4.55 (2H, s), 3.82 (2H, t, J=5.6 Hz),2.97 (2H, t, J=5.6 Hz); LRMS (ESI) m/z 408 [M+H]⁺.

Step 4 Synthesis of6-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-((1r,4r)-4-hydroxycyclohexyl)pyridazine-3-carboxamide

By reacting the compound obtained from step 3 andtrans-4-aminocyclohexanol according to Example 11, the target compoundwas obtained (5.6 mg, 50%).

¹H-NMR (DMSO-d₆) δ10.14 (1H, br-s), 8.67 (1H, d, J=8.7 Hz), 8.63 (1H,s), 8.41 (1H, d, J=9.5 Hz), 8.12 (1H, d, J=9.5 Hz), 7.70 (1H, d, J=8.7Hz), 7.33 (1H, d, J=2.2 Hz), 7.13 (1H, dd, J=8.7, 2.2 Hz), 4.60-4.52(3H, m), 3.84-3.74 (3H, m), 2.95 (2H, t, J=5.3 Hz), 1.90-1.75 (4H, m),1.56-1.45 (2H, m), 1.33-1.18 (3H, m); LRMS (ESI) m/z 505 [M+H]⁺.

Example 306-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-((1-hydroxycyclopropyl)methyl)pyridazine-3-carboxamide

By performing the same operation as Example 11 and using the compound(20 mg) obtained from Production Example B and1-(aminomethyl)cyclopropanol (34 mg), the target compound was obtained(3.6 mg, 16%).

¹H-NMR (CDCl₃) δ9.00 (1H, d, J=9.2 Hz), 8.74 (1H, s), 8.38 (1H, t, J=5.8Hz), 8.31 (1H, d, J=9.2 Hz), 8.25-8.08 (1H, m), 7.72 (1H, d, J=8.8 Hz),7.27 (1H, d, J=2.6 Hz), 7.10 (1H, dd, J=8.8, 2.6 Hz), 7.36 (1H, dd,J=8.8, 2.3 Hz), 4.57 (2H, s), 3.92 (2H, t, J=5.6 Hz), 3.69 (2H, d, J=5.8Hz), 3.00 (2H, t, J=5.6 Hz), 0.95-0.89 (2H, m), 0.77-0.70 (2H, m); LRMS(ESI) m/z 511 [M+H]⁺.

Example 312-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide

Step 1 Synthesis of2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)isonicotinicacid

By performing the same operation as Reference Examples 2-1 and 2-2 andusing ethyl 2-aminoisonicotinate (135 mg) instead of methyl6-aminonicotinate, the target compound was obtained (147 mg, two stepyield 45%).

¹H-NMR (DMSO-d₆) δ9.35 (1H, s) 8.62 (2H, s), 8.48 (1H, d, J=5.0 Hz),7.86 (1H, d, J=8.9 Hz), 7.47 (1H, dd, J=5.0, 1.1 Hz), 7.43 (1H, d, J=2.0Hz), 7.36 (1H, dd, J=8.9, 2.0 Hz), 4.57 (2H, s), 3.85 (2H, t, J=5.4 Hz),2.90 (2H, t, J=5.4 Hz); LRMS (ESI) m/z 441 [M+H]⁺.

Step 2 Synthesis of2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)isonicotinamide

The compound (25 mg) obtained from step 1 and 2,2,2-trifluoroethylamine(11 mg) were dissolved in DMF (1 mL), and added with HATU (43 mg) anddiisopropylethylamine (40 μL), followed by stirring for 3 hours at roomtemperature. The reaction solution was added with water and extractionwith ethyl acetate was performed three times. The organic layer waswashed with water and saturated brine, dried over sodium sulfate, andconcentrated. The obtained residues were purified by silica gel columnchromatography to obtain the target compound (22 mg, 73%).

¹H-NMR (CDCl₃) δ8.90 (1H, s), 8.74 (1H, s), 8.43 (1H, d, J=5.1 Hz), 7.70(1H, d, J=8.8 Hz), 7.45 (1H, s), 7.40 (1H, dd, J=5.1, 1.5 Hz), 7.25 (1H,d, J=2.6 Hz), 7.08 (1H, dd, J=8.8, 2.6 Hz), 6.71 (1H, t, J=5.9 Hz), 4.53(2H, s), 4.18 (2H, m), 3.89 (2H, t, J=5.8 Hz), 2.89 (2H, t, J=5.8 Hz);LRMS (ESI) m/z 522 [M+H]⁺.

Example 326-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyridazine-3-carboxamide

By performing the same operation as Example 11 and using the compound(20 mg) obtained from Production Example B instead of the compoundobtained from Reference Example 2-2, 1-amino-2-methylpropan-2-ol (4 mg)instead of 2,2,2-trifluoroethylamine, and HATU (26 mg) and DIPEA (15 μL)instead of DMT-MM, the target compound was obtained (4.2 mg, 18%).

¹H-NMR (CD₃OD) δ8.81 (1H, d, J=9.2 Hz), 8.65 (1H, s), 8.22 (1H, d, J=9.2Hz), 7.79 (1H, d, J=8.8 Hz), 7.41 (1H, d, J=2.6 Hz), 7.32 (1H, dd,J=2.6, 8.8 Hz), 4.64-4.54 (3H, m), 3.93 (2H, t, J=5.5 Hz), 3.47 (2H, s),3.02 (2H, t, J=5.5 Hz), 1.26 (6H, s); LRMS (ESI) m/z 513 [M+H]⁺.

Example 335-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyrazine-2-carboxamide

By performing the same operation as Example 11 and using the compound(10 mg) obtained from Production Example C instead of the compoundobtained from Reference Example 2-2 and 1-amino-2-methylpropan-2-ol (8mg) instead of 2,2,2-trifluoroethylamine, the target compound wasobtained (6.4 mg, 55%).

¹H-NMR (DMSO-d₆) δ10.04 (1H, br-s), 9.35 (1H, s), 8.92 (1H, s), 8.67(1H, s), 8.29 (1H, t, J=6.2 Hz), 7.88 (1H, d, J=8.9 Hz), 7.46 (1H, d,J=2.2 Hz), 7.39 (1H, dd, J=2.2, 8.9 Hz), 4.72 (1H, s), 4.62 (2H, s),3.87 (2H, t, J=5.5 Hz), 3.34-3.30 (2H, m), 2.94 (2H, t, J=5.5 Hz), 1.12(6H, s); LRMS (ESI) m/z 513 [M+H]⁺.

Example 342-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyrimidine-5-carboxamide

By performing the same operation as Example 11 and using the compound (5mg) obtained from Production Example D instead of the compound obtainedfrom Reference Example 2-2 and 1-amino-2-methylpropan-2-ol (4 mg)instead of 2,2,2-trifluoroethylamine, the target compound was obtained(3.2 mg, 53%).

¹H-NMR (DMSO-d₆) δ10.42 (1H, br-s), 8.95 (2H, s), 8.77 (1H, s), 8.42(1H, t, J=6.2 Hz), 7.88 (1H, d, J=8.9 Hz), 7.43 (1H, d, J=2.1 Hz), 7.36(1H, dd, J=2.1, 8.9 Hz), 4.67 (2H, s), 4.56 (1H, s), 3.79 (2H, t, J=5.5Hz), 3.24 (2H, d, J=6.2 Hz), 2.77 (2H, t, J=5.5 Hz), 1.11 (6H, s); LRMS(ESI) m/z 513 [M+H]⁺.

Example 355-((7-(4-Cano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-(1-methyl-1H-pyrazol-5-yl)ethyl)-1,3,4-thiadiazol-2-carboxamide

Step 1 Synthesis of 2-(1-methyl-1H-pyrazol-5-yl)ethyl methanesulfonate

2-(1-Methyl-1H-pyrazol-5-yl)ethanol (537 mg) obtained from step 1 ofExample 14 and triethylamine (0.89 mL) were dissolved in chloroform (10mL) and added dropwise with methanesulfonyl chloride (0.4 mL) at 0° C.The reaction solution was stirred for 6 hours at room temperature. Afteradding water to the reaction solution and extraction three times withchloroform, it was dried over sodium sulfate and concentrated. Theobtained residues were purified by silica gel column chromatography toobtain the target compound as a colorless oily product (930 mg).

¹H-NMR (CDCl₃) δ7.42 (1H, d, J=1.7 Hz), 6.14 (1H, d, J=1.7 Hz), 4.44(2H, t, J=6.7 Hz), 3.85 (3H, s), 3.11 (2H, t, J=6.7 Hz), 2.95 (3H, s);LRMS (ESI) m/z 205 [M+H]⁺.

Step 2 Synthesis of 2-(1-methyl-1H-pyrazol-5-yl)ethanamine

The compound (443 mg) obtained from step 1 was dissolved in DMF, andadded with sodium azide (705 mg), followed by stirring at 60° C. for 3hours. The reaction solution was added with water and extracted threetimes with ethyl acetate. The organic layer was washed with water andsaturated brine, dried over sodium sulfate and then concentrated. Theobtained residues were dissolved in methanol (8 mL), and added with 10%palladium/carbon (50 mg, containing 50% water), followed by stirringovernight at atmospheric pressure under hydrogen atmosphere. Thereaction solution was filtered through Hyflo Super-Cel and the solventwas concentrated to obtain the target compound (180 mg, 76%).

¹H-NMR (CDCl₃) δ7.42 (1H, J=1.7 Hz), 6.10 (1H, d, J=1.7 Hz), 3.84 (3H,s), 3.57 (2H, t, J=7.1 Hz), 2.90 (2H, t, J=7.1 Hz); LRMS (ESI) m/z 126[M+H]⁺.

Step 3 Synthesis of5-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-(1-methyl-1H-pyrazol-5-yl)ethyl)-1,3,4-thiadiazol-2-carboxamide

The compound (17 mg) obtained from step 2 and the compound (30 mg)obtained from Production Example E were dissolved in DMF, and added withEDC-HCl (25 mg) and 1-hydroxybenzotriazole (18 mg), followed by stirringovernight at room temperature. The reaction solution was added withwater and extracted three times with ethyl acetate. The organic layerwas washed with water and saturated brine, dried over sodium sulfate andthen concentrated. The obtained residues were purified by silica gelcolumn chromatography to obtain the target compound (17 mg, 46%).

¹H-NMR (CDCl₃) δ8.32 (1H, s), 7.70 (1H, d, J=8.8 Hz), 7.49 (1H, t, J=5.9Hz), 7.39 (1H, d, J=1.8 Hz), 7.24 (1H, d, J=2.4 Hz), 7.09 (1H, dd,J=8.8, 2.4 Hz), 6.11 (1H, d, J=1.8 Hz), 4.59 (2H, s), 3.91-3.71 (4H, m),3.83 (3H, s), 3.07-2.94 (4H, m); LRMS (ESI) m/z 555 [M+H]⁺.

Example 366-((7-(4-Cano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl)nicotinamide

By performing the same operation as Example 11 and using the compound(30 mg) obtained from Reference Example 2-2 and4-(trifluoromethyl)thiazol-2-yl)methanamine hydrochloride (16 mg)instead 2,2,2-trifluoroethylamine, and adding HATU (39 mg) and DIPEA (18mg) instead of DMT-MM, 20 mg of the target compound was obtained (yield48%).

¹H-NMR (DMSO-d₆) δ9.53 (1H, m), 8.84 (1H, s), 8.64 (1H, s), 8.41 (1H,s), 8.24 (2H, m), 8.11 (1H, s), 7.86 (1H, d, J=8.8 Hz), 7.43 (1H, d,J=2.2 Hz), 7.37 (1H, d, J=8.8 Hz), 4.78 (2H, d, J=6.2 Hz), 4.58 (2H, s),3.84 (2H, t, J=5.7 Hz), 2.92 (2H, t, 5.5 Hz); LRMS (ESI) m/z 605 [M+H]⁺.

Example 37(R)—N-(1-(1,3,4-Oxadiazol-2-yl)ethyl)-2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-4-(trifluoromethyl)thiazol-5-carboxamide

Step 1 Synthesis of (R)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate

Boc-D-alanine methyl ester (2.0 g) was dissolved in ethanol (50 mL), andadded with hydrazine monohydrate (0.6 mL), followed by stirringovernight. Upon the completion of the reaction, ethyl acetate and waterwere added for fractionation. The organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate. The insolublematters were separated by filtration, the filtrate was concentrated anddried, and the obtained residues were purified by silica gel columnchromatography to obtain 500 mg of the target compound (yield 25%).

¹H-NMR (DMSO-d₆) δ8.96 (1H, br-s), 6.83 (1H, d, J=7.7 Hz), 4.16 (2H,br-s), 3.91 (1H, t, 7.2 Hz), 1.36 (9H, s), 1.13 (3H, d, J=7.0 Hz); LRMS(ESI) m/z 204 [M+H]⁺.

Step 2 Synthesis of (R)-tert-butyl(1-(1,3,4-oxadiazol-2-yl)ethyl)carbamate

The compound obtained from step 1 was dissolved in triethyl orthoformate(11 mL) and stirred overnight at 150° C. After the reaction, it waspurified by silica gel column chromatography to obtain the targetcompound (960 mg) (yield 82%).

¹H-NMR (DMSO-d₆) δ9.15 (1H, s), 7.62 (1H, m), 4.87 (1H, m), 1.45 (3H, d,J=7.1 Hz), 1.38 (9H, s); LRMS (ESI) m/z 157 [M-tert butyl+H]⁺.

Step 3 Synthesis of (R)-1-(1,3,4-oxadiazol-2-yl)ethanamine

The compound (200 mg) obtained from step 2 was dissolved in1,1,1,3,3,3-hexafluoro-2-propanol (4.7 mL) and stirred for 1 hour at150° C. under irradiation of microwave. After cooling, it wasconcentrated under reduced pressure to obtain the target compound as anoily product (96 mg) (yield 91%).

¹H-NMR (DMSO-d₆) δ9.13 (1H, s), 4.18 (1H, m), 2.12 (2H, br-s), 1.38 (3H,d, J=6.8 Hz); LRMS (ESI) m/z 114 [M+H]⁺.

Step 4 Synthesis of(R)—N-(1-(1,3,4-oxadiazol-2-yl)ethyl)-2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-4-(trifluoromethyl)thiazol-5-carboxamide

By performing the same operation as Example 11 and using the compound(45 mg) obtained from Example 26 (step 2) instead of the compoundobtained from Reference Example 2-2 and(R)-1-(1,3,4-oxadiazol-2-yl)ethanamine (17 mg) obtained from step 3instead of 2,2,2-trifluoroethylamine, 29 mg of the target compound wasobtained (yield 55%).

¹H-NMR (DMSO-d₆) δ9.38 (1H, d, J=6.8 Hz), 9.19 (1H, s), 8.74 (1H, s),8.11 (1H, s), 7.84 (1H, d, J=8.9 Hz), 7.43 (1H, s), 7.36 (1H, d, J=8.9Hz), 5.33 (1H, t, J=7.2 Hz), 4.56 (2H, s), 3.84 (2H, t, J=5.5 Hz), 2.90(2H, m), 1.55 (3H, d, J=7.5 Hz) LRMS (ESI) m/z 610 [M+H]⁺.

Example 38(R)—N-(1-(1,3,4-Oxadiazol-2-yl)ethyl)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinamide

By performing the same operation as Example 11 and using the compound(30 mg) obtained from Reference Example 2-2 and the compound (15 mg)obtained from step 3 of Example 37 instead of 2,2,2-trifluoroethylamine,12 mg of the target compound was obtained (yield 33%).

¹H-NMR (DMSO-d₆) δ9.50 (1H, s), 9.18-9.11 (2H, m), 8.80 (1H, s), 8.62(1H, s), 8.24-8.17 (2H, m), 7.84 (1H, d, J=8.9 Hz), 7.42 (1H, s), 7.35(1H, d, J=8.9 Hz), 5.42 (1H, m), 4.56 (2H, s), 3.83 (2H, t, J=5.5 Hz),2.90 (2H, m), 1.60 (3H, d, J=6.8 Hz) LRMS (ESI) m/z 536 [M+H]⁺.

Example 39(R)—N-(1-(1,3,4-Oxadiazol-2-yl)ethyl)-5-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-1,3,4-thiadiazol-2-carboxamide

By performing the same operation as Example 11 and using the compoundobtained from Production Example E instead of the compound obtained fromReference Example 2-2 and the compound obtained from step 3 of Example37 instead of 2,2,2-trifluoroethylamine, the target compound wasobtained (yield 44%).

¹H-NMR (DMSO-d₆) δ9.74 (1H, d, J=7.5 Hz), 9.15 (1H, s), 8.77 (1H, s),8.10 (1H, s), 7.84 (1H, d, J=8.9 Hz), 7.43 (1H, s), 7.36 (1H, d, J=8.9Hz), 5.41 (1H, m), 4.59 (2H, s), 3.85 (2H, t, J=5.5 Hz), 2.94 (2H, m),1.62 (3H, d, J=7.5 Hz) LRMS (ESI) m/z 543 [M+H]⁺.

Example 40(R)-6-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethyl)nicotinamide

Step 1 Synthesis of (R)-tert-butyl(1-oxo-1-(2-(2,2,2-trifluoroacetyl)hydrazinyl)propan-2-yl)carbamate

The compound (400 mg) obtained from step 1 of Example 37 was dissolvedin acetonitrile (10 mL) and then added with DIPEA (0.77 mL). Undernitrogen atmosphere, it was cooled to −45° C. and added withtrifluoroacetic anhydride (0.56 mL). The temperature of the mixturesolution was gradually increased and stirred for 30 minutes at roomtemperature. The solvent was removed by concentration under reducedpressure, and ethyl acetate and water were added for fractionation. Theorganic layer was washed with saturated brine, and dried over anhydroussodium sulfate. The insoluble matters were separated by filtration, thefiltrate was concentrated and dried, and the obtained residues werepurified by silica gel column chromatography to obtain 236 mg of thetarget compound (yield 40%).

¹H-NMR (CDCl₃) δ4.90 (1H, m), 4.28 (1H, m), 1.46 (9H, s), 1.42 (3H, d,J=7.0 Hz); LRMS (ESI) m/z 243 [M-tert-butyl+H]⁺.

Step 2 Synthesis of (R)-tert-butyl(1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate

Acetonitrile suspension (7.7 mL) of the compound (230 mg) obtained fromstep 1 was added with DIPEA (780 μL) and triphenylphosphine (830 mg),followed by stirring for 5 minutes at room temperature. After beingadded with hexachloroethane (420 mg), it was stirred overnight at roomtemperature. The solvent was distilled off under reduced pressure andthe residues were added with ethyl acetate and water for fractionation.After the extraction, it was washed with saturated brine, and dried overanhydrous sodium sulfate. The insoluble matters were separated byfiltration, the filtrate was concentrated and dried, and the obtainedresidues were purified by silica gel column chromatography to obtain 142mg of the target compound (yield 65%).

¹H-NMR (CDCl₃) δ5.18-5.11 (2H, m), 1.80-1.60 (3H, m), 1.45 (9H, s)

Step 3 Synthesis of(R)-1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethanamine

The compound (140 mg) obtained from step 2 was dissolved in1,1,1,3,3,3-hexafluoro-2-propanol (2.5 mL) and stirred for 1 hour at150° C. under irradiation of microwave. After cooling, concentrationunder reduced pressure was performed to obtain the target compound as anoily product (99 mg, yield 99%).

¹H-NMR (CDCl₃) δ4.47-4.36 (3H, m), 1.63 (3H, d, J=7.0 Hz)

Step 4 Synthesis of(R)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethyl)nicotinamide

By performing the same operation as Example 11 and using the compoundobtained from step 3 instead of 2,2,2-trifluoroethylamine, the targetcompound was obtained (41%).

¹H-NMR (DMSO-d₆) δ9.53 (1H, br-s), 9.22 (1H, d, J=7.3 Hz), 8.82 (1H, s),8.64 (1H, s), 8.25-8.15 (2H, m), 7.86 (1H, d, J=9.0 Hz), 7.44 (1H, d,J=2.4 Hz), 7.36 (1H, dd, J=9.0 Hz, 2.4 Hz), 5.50 (1H, dq, J=7.3 Hz, 7.1Hz), 4.58 (2H, s), 3.85 (2H, m), 2.92 (2H, m), 1.66 (3H, d, J=7.1 Hz),LRMS (ESI) m/z 604 [M+H]⁺.

Example 414-(4-((4-(4-(2-Hydroxypropan-2-yl)piperidin-1-carbonyl)oxazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of ethyl2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)oxazol-4-carboxylate

By performing the same operation as Reference Example 2-1 and using2-aminooxazol-4-carboxylic acid ethyl ester (387 mg) instead of methyl6-aminonicotinate, and having the reaction for 20 minutes at 160° C.under irradiation of microwave instead of overnight stirring at 80° C.,the target compound was obtained (570 mg, 60%).

¹H-NMR (DMSO-d₆) δ8.30 (1H, s), 7.95 (1H, s), 7.69 (1H, d, 8.9 Hz), 7.23(1H, d, J=2.4 Hz), 7.07 (1H, dd, J=2.4, 8.9 Hz), 4.47-4.34 (4H, m), 3.74(2H, t, 5.5 Hz), 2.96 (2H, t, J=5.5 Hz), 1.39 (3H, t, J=7.2 Hz); LRMS(ESI) m/z 459 [M+H]⁺.

Step 2 Synthesis of2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)oxazol-4-carboxylicacid

The compound (550 mg) obtained from step 1 was suspended in ethanol (10mL), and added with 2.0 mol/L aqueous solution of sodium hydroxide (4.8mL), followed by stirring for 6 hours at 60° C. The reaction solutionwas concentrated and diluted with distilled water. By using 2.0 mol/Lhydrochloric acid, the pH was adjusted to about 5. The precipitatedsolid was collected by filtration to obtain the target compound (495 mg,96%).

LRMS (ESI) m/z 431 [M+H]⁺.

Step 3 Synthesis of4-(4-((4-(4-(2-hydroxypropan-2-yl)piperidin-1-carbonyl)oxazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Example 11 and using the compound(15 mg) obtained from step 2 instead of the compound obtained fromReference Example 2-2, 2-(piperidin-4-yl)propan-2-ol (6 mg) instead of2,2,2-trifluoroethylamine, and HATU (20 mg) and DIPEA (12 μL) instead ofDMT-MM, the target compound was obtained (4.8 mg, 25%).

¹H-NMR (CD₃OD) δ8.40 (1H, s), 7.99 (1H, br-s), 7.95-7.85 (1H, m), 7.77(1H, d, J=8.8 Hz), 7.38 (1H, d, J=2.3 Hz), 7.29 (1H, dd, J=2.3, 8.8 Hz),4.75-4.60 (2H, m), 4.48 (2H, br-s), 3.84-3.80 (2H, m), 3.32-3.24 (2H,m), 2.90-2.65 (3H, m), 1.95-1.80 (2H, m), 1.66-1.58 (1H, m), 1.41-1.25(2H, m), 1.17 (6H, s); LRMS (ESI) m/z 556 [M+H]⁺.

Example 424-(4-((5-(4-(2-Hydroxypropan-2-yl)piperidin-1-carbonyl)oxazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of ethyl2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)oxazol-5-carboxylate

By performing the same operation as Reference Example 2-1 and using2-aminooxazole-5-carboxylic acid ethyl ester (276 mg) instead of methyl6-aminonicotinate, and having the reaction for 25 minutes at 160° C.under irradiation of microwave instead of overnight stirring at 80° C.,the target compound was obtained (180 mg, 27%).

¹H-NMR (CDCl₃) δ8.28 (1H, s), 7.68-7.77 (3H, s), 7.23 (1H, d, 2.6 Hz),7.08 (1H, dd, J=2.6, 8.8 Hz), 4.45-4.36 (4H, m), 3.75 (2H, t, 5.7 Hz),2.98 (2H, t, J=5.7 Hz), 1.39 (3H, t, J=7.2 Hz); LRMS (ESI) m/z 459[M+H]⁺.

Step 2 Synthesis of2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)oxazol-5-carboxylicacid

By performing the same operation as step 2 of Example 41 and using thecompound (180 mg) obtained from step 1 of this Example instead of thecompound obtained from step 1 of Example 41, the target compound wasobtained (137 mg, 81%).

LRMS (ESI) m/z 431 [M+H]⁺.

Step 3 Synthesis of4-(4-((5-(4-(2-hydroxypropan-2-yl)piperidin-1-carbonyl)oxazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Example 11 and using the compound(25 mg) obtained from step 2 instead of the compound obtained fromReference Example 2-2, 2-(piperidin-4-yl)propan-2-ol (10 mg) instead of2,2,2-trifluoroethylamine, and HOBt (10 mg) and WSC (13 mg) instead ofDMT-MM, the target compound was obtained (8.6 mg, 27%).

¹H-NMR (CDCl₃) δ8.26 (1H, s), 7.69 (1H, d, J=8.8 Hz), 7.60 (1H, s),7.29-7.21 (1H, m), 7.07 (1H, dd, J=2.2, 8.8 Hz), 4.75-4.60 (2H, m), 4.42(2H, s), 3.75 (2H, t, J=5.7 Hz), 3.06-2.92 (2H, m), 1.94-1.86 (2H, m),1.61 (2H, dt, J=2.9, 12.1 Hz), 1.39-1.16 (9H, m); LRMS (ESI) m/z 556[M+H]⁺.

Example 434-(4-((5-(4-(2-Hydroxypropan-2-yl)piperidin-1-carbonyl)-1,3,4-oxadiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of ethyl5-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-1,3,4-oxadiazol-2-carboxylate

By performing the same operation as Reference Example 2-1 and using5-amino-1,3,4-oxadiazol-2-carboxylic acid ethyl ester (418 mg) insteadof methyl 6-aminonicotinate, and having the reaction for 30 minutes at150° C. under irradiation of microwave instead of overnight stirring at80° C., the target compound was obtained (120 mg, 15%).

¹H-NMR (DMSO-d₆) δ8.59 (1H, s), 7.88 (1H, d, 8.8 Hz), 7.46 (1H, d, 2.6Hz), 7.38 (1H, dd, J=2.6, 8.8 Hz), 4.55 (2H, s), 4.40 (2H, q, 7.0 Hz),3.83 (2H, t, J=5.9 Hz), 2.80 (2H, t, J=5.9 Hz), 1.34 (3H, t, J=7.0 Hz);LRMS (ESI) m/z 460 [M+H]⁺.

Step 2 Synthesis of4-(4-((5-(4-(2-hydroxypropan-2-yl)piperidin-1-carbonyl)-1,3,4-oxadiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (30 mg) obtained from step 1 was dissolved in ethanol (2mL) and THF (2 mL), and added with 1.0 mol/L aqueous solution of sodiumhydroxide (130 μL), followed by stirring for 5 minutes at roomtemperature. The reaction solution was ice-cooled and adjusted to have apH of about 5 by using 1.0 mol/L hydrochloric acid, followed byconcentration and drying. The obtained solid was dissolved in methanol(1 mL) and DMF (1 mL), and added with 2-(piperidin-4-yl)propan-2-ol (11mg) and DMT-MM (21 mg), followed by stirring overnight at roomtemperature. The reaction solution was added with2-(piperidin-4-yl)propan-2-ol (10 mg) and DMT-MM (88 mg) and furtherstirred at room temperature for 6 hours. The reaction solution was addedwith water, and the precipitates were collected by filtration. Theobtained solid was purified by silica gel column chromatography toobtain the target compound (5.0 mg, 14%).

¹H-NMR (DMSO-d₆) δ8.56 (1H, br-s), 7.87 (1H, d, J=8.8 Hz), 7.46 (1H, d,J=2.2 Hz), 7.38 (1H, dd, J=2.2, 8.8 Hz), 4.69-4.43 (4H, m), 4.20 (1H,s), 3.81 (2H, t, J=5.7 Hz) 3.17-3.04 (1H, m), 2.85-2.61 (3H, m), 1.80(2H, t, J=12.8 Hz), 1.57-1.45 (1H, m), 1.31-1.12 (2H, m), 1.03 (6H, s);LRMS (ESI) m/z 557 [M+H]⁺.

Example 442-Bromo-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

Step 1 Synthesis of methyl6-((7-benzyl-5,6,7,8-tetrahydropyrodopyrido[3,4-d]pyrimidin-4-yl)amino)nicotinate

According to Reference Example 2-1, commercially available7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (5.37 g),methyl 6-aminonicotinate (3.45 g), Pd(dba)₂ (1.19 g), dppf (1.15 g), andpotassium carbonate (5.70 g) were suspended in 1,2-dimethoxyethane (100mL) and stirred for 1 hour at 83° C. under nitrogen atmosphere. Afterthe reaction solution was cooled to room temperature, it was added withwater (400 mL). The resulting solid was collected by filtration andsuspended and washed with methanol/water (3/1, 60 mL), followed bysuspending and washing with toluene (60 mL). After drying by heating,the target compound was obtained (5.18 g, yield 67%).

¹H-NMR (DMSO-d₆) δ9.39 (1H, s), 8.84 (1H, s), 8.57 (1H, s), 8.32 (1H, d,J=8.0 Hz), 8.26 (1H, dd, J=8.0, 4.0 Hz), 7.40-7.20 (5H, m), 3.86 (3H,s), 3.69 (2H, s), 3.48 (2H, s), 2.80-2.70 (4H, m); LRMS (ESI) m/z 376[M+H]⁺.

Step 2 Synthesis of2-(6-((7-benzyl-5,6,7,8-tetrahydropyridopyrodo[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol

Under nitrogen atmosphere, the compound (5.0 g) obtained from step 1 wassuspended in THF (16 mL), and under ice cooling, a THF solution (47 mL)of 1 mol/L methyl magnesium bromide was added dropwise thereto over 5minutes. After the dropwise addition was completed, the temperature wasraised to room temperature and the reaction solution was stirred at thesame temperature for 3.5 hours. The reaction solution was again cooledunder ice cooling, and added with 2 mol/L hydrochloric acid (24 mL) at atemperature of 20° C. or less. The insoluble matters were removed byCelite, and the oil layer obtained by layer fractionation was dried overmagnesium sulfate and the solvent was distilled off under reducedpressure. The obtained oily product was added with m-xylene (25 mL) andstirred under ice cooling to precipitate the solid. The precipitatedproduct was collected by filtration, followed by drying by heating toobtain the target compound (2.44 g, yield 49%).

¹H-NMR (DMSO-d₆) δ8.78 (1H, s), 8.44 (1H, s), 8.40 (1H, d, J=4.0 Hz),8.07 (1H, d, J=8.0 Hz), 7.82 (1H, dd, J=8.0, 4.0 Hz), 7.40-7.25 (5H, m),5.14 (1H, s), 3.68 (2H, s), 3.43 (2H, s), 2.80-2.65 (4H, m), 1.45 (6H,s); LRMS (ESI) m/z 376 [M+H]+

Step 3 Synthesis of2-(6-((5,6,7,8-tetrahydropyridopyrodo[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol

The compound (1.0 g) obtained from step 2 was dissolved in ethanol (10mL), and added with 10% palladium/carbon (50% wet product, 600 mg),followed by stirring at 60° C. for 7 hours under hydrogen atmosphere.The insoluble matters were removed by Celite, and the filtrate wasconcentrated. The obtained oily product was added with methyl isobutylketone (12 mL) and the precipitates were obtained by cooling. The solidwas collected by filtration, and dried and heated under reduced pressureto obtain the precipitates, which were collected by filtration to obtainthe target compound (576 mg, yield 76%).

Step 4 Synthesis of2-bromo-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The compound (20 mg) obtained from step 3, 2-bromo-4-fluorobenzonitrile(21 mg), and potassium carbonate (15 mg) were dissolved in DMSO (0.2mL), and stirred at 125° C. for 25 minutes under microwave irradiation.The reaction mixture was purified by reverse phase preparative HPLCcolumn chromatography, and the obtained fraction was concentrated underreduced pressure to obtain the target compound as a white amorphousproduct (15 mg, 46%).

¹H-NMR (CDCl₃) δ8.67 (1H, s), 8.47 (1H, d, J=8.8 Hz), 8.42 (1H, d, J=2.6Hz), 7.87 (1H, dd, J=8.8, 2.6 Hz), 7.51 (1H, d, J=8.8 Hz), 7.36 (1H,br-s), 7.17 (1H, d, J=2.6 Hz), 6.89 (1H, dd, J=8.8, 2.6 Hz), 4.45 (2H,s), 3.81 (2H, t, J=5.9 Hz), 2.83 (2H, t, J=5.7 Hz), 1.62 (6H, s); LRMS(ESI) m/z 465 [M+H]⁺.

Example 452-Chloro-4-(4-((4-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

Step 1 Synthesis of 4-fluoro-5-iodopyridin-2-amine

4-Fluoropyridin-2-amine (1.20 g) was dissolved in acetonitrile (24 mL),and added with N-iodosuccinimide (2.41 g) under ice cooling and lightblocking conditions, followed by stirring overnight at room temperature.The obtained reaction solution was concentrated and purified by silicagel column chromatography to obtain 132 mg (5%) of the target compoundas a pale yellow solid.

Step 2 Synthesis of ethyl 6-amino-4-fluoropyridin-3-carboxylate

The compound (132 mg) obtained from step 1, palladium acetate (II) (31mg), dppf (77 mg), and triethylamine (0.23 mL) were suspended in ethanol(26 mL), and stirred at 60° C. for two days and nights under carbonmonoxide atmosphere (0.5 MPa). The reaction solution was concentratedunder reduced pressure, and added with ethyl acetate (20 mL) anddistilled water (20 mL), followed by filtration through Celite. Theorganic layer was washed with distilled water and saturated brine, anddried over anhydrous sodium sulfate. The insoluble matters wereseparated by filtration, and the filtrate was concentrated and dried.The obtained solid was purified by silica gel column chromatography toobtain 67 mg (66%) of the target compound as a grayish white solid.

Step 3 Synthesis of ethyl6-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyridopyrodo[3,4-d]pyrimidin-4-yl)amino)-4-fluoronicotinate

The compound (139 mg) obtained from Reference Example 1-3, the compound(60 mg) obtained from step 2, Pd₂(dba)₃ (30 mg), XantPhos (38 mg), andcesium carbonate (318 mg) were suspended in dioxane (1.2 mL), andstirred for 4 hours at 80° C. under nitrogen atmosphere. The reactionsolution was cooled to room temperature and filtered through Celite. Thefiltrate was concentrated and the obtained solid was purified by silicagel column chromatography to obtain 14 mg (9%) of the target compound asa pale yellow solid.

Step 4 Synthesis of2-chloro-4-(4-((4-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The compound (14 mg) obtained from step 3 was dissolved in THF (1.4 mL),and added with methyl magnesium bromide (3 mol/L diethyl ether solution,0.11 mL) in an ice bath, followed by stirring at room temperature for 1hour. The reaction solution was added with a saturated aqueous solutionof ammonium chloride (3 mL), followed by extracting three times withchloroform. The organic layer was combined, dried over magnesiumsulfate, the insoluble matters were separated by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residueswere purified by reverse phase preparative HPLC column chromatography toobtain 2.1 mg (16%) of the target compound as a yellow solid.

¹H-NMR (CDCl₃) δ8.70 (1H, s), 8.47 (1H, d, J=11.0 Hz), 8.37 (1H, d,J=14.3 Hz), 7.53 (1H, d, J=8.8 Hz), 7.45 (1H, br-s), 6.99 (1H, d, J=2.6Hz), 6.85 (1H, dd, J=8.8, 2.6 Hz), 4.47 (2H, s), 3.81 (2H, t, J=5.9 Hz),2.83 (2H, t, J=5.7 Hz), 1.67 (6H, s); LRMS (ESI) m/z 439 [M+H]⁺.

Example 462-Chloro-4-(4-((6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

Step 1 Synthesis of ethyl 6-amino-2-fluoronicotinate

By performing the same operation as step 2 of Example 5 and usingethanol instead of methanol, the target compound was obtained.

Step 2 Ethyl6-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2-fluoronicotinate

By performing the same operation as Reference Example 2-1 and using thecompound obtained from Reference Example 1-2 and the compound obtainedfrom step 1, the target compound was obtained.

Step 32-Chloro-4-(4-((6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

By performing the same operation as step 4 of Example 45 and using thecompound (30 mg) obtained from step 3, the target compound was obtainedas a white solid (4.2 mg, 14%).

¹H-NMR (CDCl₃) δ8.70 (1H, s), 8.39 (1H, dd, J=8.4, 1.8 Hz), 8.06 (1H,dd, J=10.6, 8.4 Hz), 7.53 (1H, d, J=8.8 Hz), 7.00 (1H, d, J=2.6 Hz),6.85 (1H, dd, J=8.8, 2.6 Hz), 4.47 (2H, s), 3.81 (2H, t, J=5.7 Hz), 2.80(2H, t, J=5.7 Hz), 1.65 (6H, s); LRMS (ESI) m/z 439 [M+H]⁺.

Example 474-(4-((4-Fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Example 46 and using ethyl6-amino-4-fluoronicotinate, which had been synthesized according to step2 of Example 5 by using 4-fluoropyridin-2-amine instead of6-fluoropyridin-2-amine, and using the compound obtained from ReferenceExample 1-2 instead of the compound obtained from Reference Example 1-3,the target compound was obtained as a white solid (21.3 mg, 20%).

¹H-NMR (CDCl₃) δ8.70 (1H, s), 8.47 (1H, d, J=11.0 Hz), 8.37 (1H, d,J=14.3 Hz), 7.70 (1H, d, J=8.4 Hz), 7.45 (1H, br-s), 7.25 (1H, d, J=2.6Hz), 7.08 (1H, dd, J=8.6, 2.6 Hz), 4.47 (2H, s), 3.80 (2H, t, J=6.0 Hz),2.83 (2H, t, J=5.8 Hz), 1.67 (6H, s); LRMS (ESI) m/z 473 [M+H]⁺.

Example 485-((7-(4-Cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2-difluoroethyl)picolinamide

Step 1 Synthesis of5-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)picolinicacid

By performing the same operation as Reference Examples 2-1 and 2-2 andusing methyl 5-aminopicolinate (540 mg) instead of methyl6-aminonicotinate, the target compound was obtained (496 mg, two stepyield 38%).

Step 2 Synthesis of5-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2-difluoroethyl)pyridin-3-yl)picolinamide

By performing the same operation as Example 11 and using the compound(40 mg) obtained from step 1 instead of the compound obtained fromReference Example 2-2, HATU (69 mg) and DIPEA (63 uL) instead of DMT-MM,and 2,2-difluoroethylamine instead of 2,2,2-trifluoroethylamine, thetarget compound was obtained (24 mg) (yield 52%).

¹H-NMR (DMSO-d₆) δ9.13 (br-s, 1H), 8.97 (d, J=2.2 Hz, 1H), 8.94 (t,J=6.2 Hz, 1H), 8.55 (s, 1H), 8.41 (dd, J=8.6, 2.4 Hz, 1H), 8.02 (d,J=8.6 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.45 (brd, J=2.2 Hz, 1H), 7.39(dd, J=9.1, 2.2 Hz, 1H), 5.94-6.33 (m, 1H), 4.57 (s, 2H), 3.90 (brt,J=5.5 Hz, 2H), 3.63-3.74 (m, 2H), 3.25 (br-s, 1H), 2.87 (t, J=5.5 Hz,2H); LRMS (ESI) m/z 504 [M+H]⁺.

Example 496-((7-(3-Chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide

By reacting the compound (9.0 mg) obtained from step 3 of Example 29with 2,2,2-trifluoroethylamine (4.4 mg) according to Example 29, thetarget compound was obtained (7.0 mg, 65%).

¹H-NMR (DMSO-d₆) δ10.27 (br-s, 1H), 9.58 (t, J=6.6 Hz, 1H), 8.65 (s,1H), 8.47 (d, J=9.5 Hz, 1H), 8.18 (d, J=9.5 Hz, 1H), 7.70 (d, J=9.0 Hz,1H), 7.33 (d, J=2.4 Hz, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 4.56 (s, 2H),4.06-4.17 (m, 2H), 3.82 (t, J=5.6 Hz, 2H), 2.97 (brt, J=5.6 Hz, 2H);LRMS (ESI) m/z 489 [M+H]⁺.

Example 504-(4-((5-Fluoro-6-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Example 15 and using2-chloro-3-fluoro-5-nitropyridine (100 mg) instead of2-chloro-5-nitropyridine and 2-methyl-2-(1H-tetrazol-1-yl)propan-1-ol(97 mg) obtained from step 1 of Example 16 instead of2-(1H-1,2,3-triazol-1-yl)ethanol, the target compound was obtained (40mg, 49%).

¹H-NMR (DMSO-d₆) δ9.59 (s, 1H), 8.82 (br-s, 1H), 8.43 (s, 1H), 8.14 (d,J=2.2 Hz, 1H), 8.05 (dd, J=12.1, 2.2 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H),7.44 (d, J=2.6 Hz, 1H), 7.38 (dd, J=8.8, 2.6 Hz, 1H), 4.67 (s, 2H), 4.52(s, 2H), 3.88 (t, J=5.7 Hz, 2H), 2.78 (brt, J=5.5 Hz, 2H), 1.77 (s, 6H);LRMS (ESI) m/z 555 [M+H]⁺.

Example 514-(4-((5-Fluoro-6-(2-methyl-2-(1H-1,2,3-triazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of ethyl 2-methyl-2-(1H-1,2,3-triazol-1-yl)propanoate

Ethyl 2-azide-2-methylpropanoate (3.1 g) was dissolved in toluene (190mL), and added with ethynyltrimethylsilane (13 mL), followed by stirringat 130° C. for 36 hours. The reaction solution was concentrated anddried, and the obtained residues were purified by silica gel columnchromatography to obtain a crude oily product (2.16 g). The obtainedoily product was dissolved in THF (20 mL), and added with a THF solution(9.8 mL) of 1.0 mol/L tetrabutylammomnium fluoride, followed by stirringfor 15 hours at room temperature. The reaction solution was added with aTHF solution (3.0 mL) of 1.0 mol/L tetrabutylammomnium fluoride,followed by stirring for 7 hours at room temperature. The reactionmixture was added with a saturated aqueous solution of ammoniumchloride, extracted with ethyl acetate, and dried over anhydrous sodiumsulfate. The insoluble matters were separated by filtration, and thefiltrate was concentrated and dried. The obtained residues were purifiedby silica gel column chromatography to obtain the target product (500mg, 42%).

Step 2 Synthesis of 2-methyl-2-(1H-1,2,3-triazol-1-yl)propan-1-ol

The compound (420 mg) obtained from step 1 was dissolved in THF (10 mL),and then added with a THF solution (10 mL) of lithium aluminum hydroxide(130 mg) under ice cooling. After stirring for 2 hours under icecooling, water (132 μL), 1.0 mol/L aqueous solution of sodium hydroxide(132 μL), and water (400 μL) were added dropwise thereto. The reactionsolution was filtered through Celite and washed with ethyl acetate. Thefiltrate was concentrated and dried, and the obtained residues werepurified by silica gel column chromatography to obtain the targetproduct (240 mg, 74%).

Step 3 Synthesis of4-(4-((5-fluoro-6-(2-methyl-2-(1H-1,2,3-triazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Example 15 and using2-chloro-3-fluoro-5-nitropyridine (100 mg) instead of2-chloro-5-nitropyridine and2-methyl-2-(1H-1,2,3-triazol-1-yl)propan-1-ol (80 mg) obtained from step2 instead of 2-(1H-1,2,3-triazol-1-yl)ethanol, the target compound wasobtained (54 mg, 66%).

¹H-NMR (DMSO-d₆) δ8.82 (br-s, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 8.17 (d,J=2.1 Hz, 1H), 8.05 (dd, J=12.3, 2.1 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H),7.71 (s, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.38 (dd, J=8.8, 2.4 Hz, 1H), 4.66(s, 2H), 4.52 (br-s, 2H), 3.89 (t, J=5.6 Hz, 2H), 2.78 (brt, J=5.6 Hz,2H), 1.73 (s, 6H); LRMS (ESI) m/z 554 [M+H]⁺.

Example 524-(4-((5-Chloro-6-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

By performing the same operation as Example 15 and using2,3-dichloro-5-nitropyridine (100 mg) instead of2-chloro-5-nitropyridine and 2-methyl-2-(1H-tetrazol-1-yl)propan-1-ol(88 mg) obtained from step 1 of Example 16 instead of2-(1H-1,2,3-triazol-1-yl)ethanol, the target compound was obtained (33mg, 39%).

¹H-NMR (DMSO-d₆) δ9.58 (s, 1H), 8.79 (s, 1H), 8.44 (s, 1H), 8.30 (d,J=2.5 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.44 (d,J=2.2 Hz, 1H), 7.39 (dd, J=8.8, 2.5 Hz, 1H), 4.64 (s, 2H), 4.52 (br-s,2H), 3.89 (t, J=5.6 Hz, 2H), 2.78 (brt, J=5.6 Hz, 2H), 1.79 (s, 6H);LRMS (ESI) m/z 571 [M+H]⁺.

Example 532-Chloro-4-(4-((5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

By performing the same operation as step 4 of Example 17 and using thecompound (42 mg) obtained from step 3 of Example 17 and the compound (50mg) obtained from Reference Example 1-3 instead of the compound obtainedfrom Reference Example 1-2, the target compound was obtained (27 mg,33%).

¹H-NMR (DMSO-d₆) δ9.61 (s, 1H), 8.97 (br-s, 1H), 8.47 (s, 1H), 7.97-8.02(m, 2H), 7.67 (d, J=9.2 Hz, 1H), 7.40 (dd, J=9.0, 3.1 Hz, 1H), 7.29 (d,J=2.2 Hz, 1H), 7.09 (dd, J=9.2, 2.2 Hz, 1H), 4.45 (br-s, 2H), 4.36 (s,2H), 3.78 (t, J=5.6 Hz, 2H), 2.80 (brt, J=5.6 Hz, 2H), 1.77 (s, 6H);LRMS (ESI) m/z 503 [M+H]⁺.

Example 542-Chloro-4-(4-((4-methoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The solid (5.0 mg) obtained from Reference Example 1-3,4-methoxyaniline(11 g), and (+)-10-camphorsulfonic acid (3.8 mg) were suspended in2-propanol (1 mL), and under microwave irradiation, stirred for 1 hourat 120° C. The reaction solution was concentrated and dried undernitrogen stream, and the residues were purified by reverse phasepreparative HPLC column chromatography, and the obtained fraction wasconcentrated under reduced pressure to obtain the target compound (1.7mg, 26%).

¹H-NMR (400 MHz, CDCl₃) δ:8.54 (1H, s), 7.52 (1H, d, J=9.2 Hz), 7.41(2H, brd, J=8.8 Hz), 6.99 (1H, s), 6.93 (2H, d, J=8.8 Hz), 6.84 (1H,brd, J=9.2 Hz), 6.34 (1H, br-s), 4.45 (2H, s), 3.82 (3H, s), 3.78-3.84(2H, m), 2.73 (2H, br-s); LRMS (ESI) m/z 392 [M+H]⁺.

Example 552-Chloro-4-(4-((3-methoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The solid (12 mg) obtained from Reference Example 1-3,3-methoxyaniline(15 mg), and (+)-10-camphorsulfonic acid (5.3 mg) were suspended intert-butanol (1 mL), and under microwave irradiation, stirred for 45minutes at 115° C. The reaction solution was concentrated and driedunder nitrogen stream, and the residues were purified by reverse phasepreparative HPLC column chromatography, and the obtained fraction wasconcentrated under reduced pressure to obtain the target compound (5.5mg, 36%).

¹H-NMR (DMSO-d₆) δ8.80 (1H, s), 7.52 (1H, d, J=9.2 Hz), 7.45-7.58 (2H,m), 7.07 (1H, brd, J=9.2 Hz), 6.99 (1H, s), 6.85 (1H, d, J=7.1 Hz), 6.72(1H, d, J=7.2 Hz), 6.48 (1H, br-s), 4.45 (2H, s), 3.84 (3H, s),3.78-3.84 (2H, m), 2.67-2.84 (2H, m); LRMS (ESI) m/z 392 [M+H]⁺.

Example 562-Chloro-4-(4-((6-fluoro-5-(1-hydroxycyclobutyl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

Step 1 Synthesis of 1-(6-chloro-2-fluoro-3-pyridyl)cyclobutanol

A THF solution (15 mL) of 2-chloro-6-fluoropyridine (910 mg) was cooledto −78° C., and then added dropwise with LDA (2 mol/L THF solution, 5.2mL). The reaction solution was stirred at −78° C. for 45 minutes, andadded dropwise with cyclobutanone (480 mg), followed by stirring at −78°C. for 90 minutes. The reaction solution was added with ethyl acetateand water, and the organic layer was washed sequentially with asaturated aqueous solution of ammonium chloride and saturated brine, anddried over anhydrous sodium sulfate. The insoluble matters wereseparated by filtration, and the filtrate was concentrated and dried.The obtained residues were purified by silica gel column chromatographyto obtain the target compound as a colorless oily product (1.5 g).

Step 2 Synthesis of 1-(6-amino-2-fluoro-3-pyridyl)cyclobutanol

The compound (200 mg) obtained from step 1 and copper oxide (I) (30 mg)were suspended in a mixed solvent of NMP (2 mL) and 28% ammonia water,and stirred for 2 hours at 110° C. under irradiation of microwave. Thesolvent was distilled off under reduced pressure and the residues werepurified by silica gel column chromatography to obtain the targetcompound (8.4 mg, 4.6%).

Step 3 Synthesis of2-chloro-4-(4-((6-fluoro-5-(1-hydroxycyclobutyl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

By performing the same operation as Reference Example 2-1 and using thesolid (7.2 mg) obtained from Reference Example 1-3 instead of thecompound obtained from Reference Example 1-2 and the compound (4.2 mg)obtained from step 2 instead of methyl 6-aminonicotinate, the targetcompound was obtained as a yellow amorphous product (2.0 mg, 19%).

¹H-NMR (CDCl₃) δ8.71 (1H, s), 8.40 (1H, dd, J=8.8, 2.2 Hz), 7.86 (1H,dd, J=11.0, 8.1 Hz), 7.53 (1H, d, J=8.1 Hz), 7.00 (1H, d, J=2.2 Hz),6.85 (1H, dd, J=8.8, 2.2 Hz), 4.48 (2H, s), 3.75-3.86 (2H, m), 2.76-2.86(2H, m), 2.56-2.72 (2H, m), 2.33-2.48 (2H, m), 2.07-2.22 (2H, m); LRMS(ESI) m/z 451 [M+H]⁺.

Example 574-(4-((2-Hydroxypropan-2-yl)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of4-(4-((4-acetylphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (8.2 mg) obtained from Reference Example 1-2,1-(4-aminophenyl)ethanone (8.3 mg), and (+)-10-camphorsulfonic acid (2.9mg) were suspended in tert-butanol (1 mL), and under microwaveirradiation, stirred for 90 minutes at 135° C. The reaction solution wasconcentrated and dried under nitrogen stream, and the residues werepurified by reverse phase preparative HPLC column chromatography, andthe obtained fraction was concentrated under reduced pressure to obtainthe target compound (7.9 mg, 75%).

Step 2 Synthesis of4-(4-((2-hydroxypropan-2-yl)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

A THF solution (0.5 mL) of the compound (2.5 mg) obtained from step 1was added with methylmagnesium bromide (2 M THF solution, 0.1 mL) atroom temperature, and the reaction solution was stirred for 15 minutesat room temperature. The reaction solution was concentrated and driedunder nitrogen stream, and the residues were purified by reverse phasepreparative HPLC column chromatography, and the obtained fraction wasconcentrated under reduced pressure to obtain the target compound as awhite solid (1.8 mg, 69%).

¹H-NMR (CDCl₃) δ8.60 (1H, s), 7.70 (1H, d, J=8.8 Hz), 7.53 (4H, s), 7.24(1H, d, J=2.0 Hz), 7.07 (1H, dd, J=8.8, 2.0 Hz), 6.42 (1H, s), 4.51 (2H,s), 3.89 (2H, t, J=5.6 Hz), 2.78 (2H, t, J=5.6 Hz), 1.61 (6H, s); LRMS(ESI) m/z 454 [M+H]⁺.

Example 584-(4-((1-Hydroxyethyl)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

A methanol solution (0.5 mL) of the compound (1.7 mg) obtained fromExample 57 (step 1) was added with sodium tetrahydroborate (3 mg) atroom temperature, and the reaction solution was stirred for 15 minutesat room temperature. The reaction solution was concentrated and driedunder nitrogen stream, and the residues were purified by reverse phasepreparative HPLC column chromatography, and the obtained fraction wasconcentrated under reduced pressure to obtain the target compound as awhite solid (1.6 mg, 94%).

¹H-NMR (CDCl₃) δ8.60 (1H, s), 7.70 (1H, d, J=8.8 Hz), 7.53-7.60 (2H, m),7.38-7.46 (2H, m), 7.20-7.30 (1H, m), 7.03-7.13 (1H, m), 6.42 (1H, d,9.2 Hz), 4.88-4.98 (1H, m), 4.51 (2H, s), 3.85-3.93 (2H, m), 2.75-2.85(2H, m), 1.49-1.56 (3H, m); LRMS (ESI) m/z 440 [M+H]⁺.

Comparative Example 1N-(4-Cyano-3-(trifluoromethyl)phenyl)-3-((4-fluorophenyl)sulfonyl)-2-hydroxy-2-methylpropanamide(Bicalutamide)

Synthesis was performed according to the method described in J. Org.Chem., 2003, 68 (26): 10181-2.

Comparative Example 24-(4-((4-Isopropoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol

Ethyl 1-benzyl-4-oxopiperidin-3-carboxylate hydrochloride (5.31 g) wasadded with formamidine hydrochloride (1.67 g) and sodium methoxide (30mL, 28% methanol solution), and stirred overnight at 85° C. The reactionsolution was added with water and extracted 5 times with chloroform,dried over sodium sulfate, and concentrated to obtain the targetcompound (3.16 g, 77%).

¹H-NMR (DMSO-d₆) δ7.81 (1H, s), 7.32-7.23 (5H, m), 3.58 (2H, s), 3.09(2H, s), 2.58 (2H, t, J=5.7 Hz), 2.43 (2H, t, J=5.7 Hz); LRMS (ESI) m/z242 [M+H]⁺.

Step 2 Synthesis of(4-(4-Hydroxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (3.16 g) obtained from step 1 was dissolved in methanol (8mL), and added with 10% palladium/carbon (600 mg, containing 50% water)and ammonium formate (4.13 g), followed by stirring for 2 days at 60° C.The reaction solution was filtered through Hyflo Super-Cel, the residueswere washed with methanol and DMSO, and the methanol in the filtrate wasdistilled off under reduced pressure. The obtained solution was addedwith 4-fluoro-2-(trifluoromethyl)benzonitrile (2.70 g), and stirred for2 days at 40° C. The reaction solution was added with water, andextracted three times with ethyl acetate, and the organic layer waswashed with water and saturated brine. The obtained solution was driedover sodium sulfate, followed by concentration under reduced pressure toobtain the target compound (4.03 g, 44%).

¹H-NMR (DMSO-d₆) δ8.07 (1H, s), 7.85 (1H, d, J=8.9 Hz), 7.34 (1H, d,J=2.2 Hz), 7.28 (1H, dd, J=8.9, 2.2 Hz), 4.20 (2H, s), 3.75 (2H, t,J=5.6 Hz), 2.72 (2H, t, J=5.6 Hz); LRMS (ESI) m/z 321 [M+H]⁺.

Step 3 Synthesis of(4-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (1.82 g) obtained from step 2 was dissolved in1,2-dichloroethane (10 mL), and added with phosphorus oxychloride (5.3mL) and triethylamine (1.73 mL), followed by stirring for 2 hours at 90°C. The reaction solution was poured into ice water, and by carefullyadding solid potassium carbonate, neutralization was carried out. Theobtained solution was extracted three times with chloroform, dried oversodium sulfate, and concentrated under reduced pressure. The obtainedresidues were purified by silica gel column chromatography to obtain thetarget compound (1.09 g, 57%).

LRMS (ESI) m/z 339 [M+H]⁺.

Step 4 Synthesis of4-(4-((4-isopropoxyphenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (60 mg) obtained from step 3 was dissolved in acetonitrile(1.5 mL), and added with 4-isopropoxyaniline (40 mg), followed bystirring for 30 minutes at 180° C. under microwave irradiation. Thereaction solution was added with a saturated aqueous solution of sodiumhydrogen carbonate, extracted three times with chloroform, and theorganic layer was dried over sodium sulfate and concentrated. Theobtained residues were purified by silica gel column chromatography toobtain the target compound (82 mg, 100%).

¹H-NMR (DMSO-d₆) δ8.57 (1H, s), 7.69 (1H, d, J=8.8 Hz) 7.41-7.37 (2H,m), 7.23 (1H, d, J=2.6 Hz), 7.10 (1H, dd, J=8.8, 2.6 Hz), 6.95-6.90 (2H,m), 6.30 (1H, b-rs), 4.55 (1H, sept, J=6.1 Hz), 4.30 (2H, s), 3.82 (2H,t, J=5.9 Hz), 3.06 (2H, t, J=5.9 Hz), 1.36 (6H, d, J=6.1 Hz); LRMS (ESI)m/z 454 [M+H]⁺.

Comparative Example 34-(3-((4-Isopropoxyphenyl)amino)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

Step 1 Synthesis of 2-chloro-3-hydrazinylpyrazine

2,3-Dichloropyrazine (25 g) was dissolved in ethanol (500 mL), and addedwith hydrazine monohydrate (16.7 mL), followed by stirring for 1.5 hoursunder reflux. The reaction solution was added with water, and theprecipitated solid was collected by filtration and dried under reducedpressure. By recrystallizing the obtained solid from ethanol, the targetcompound was obtained (18.12 g, 74%).

Step 2 Synthesis of 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine

A mixture of the compound (8 g) obtained from step 1 and triethylorthoformate (32 mL) was stirred for 4 hours under reflux. The reactionsolution was cooled to room temperature, and the precipitated solid wasfiltered, washed with ethanol, and dried under reduced pressure toobtain the target compound (8.10 g, 95%).

¹H-NMR (DMSO-d₆) δ9.53 (1H, s), 8.62 (1H, d, J=4.6 Hz), 7.76 (1H, d,J=4.6 Hz); LRMS (ESI) m/z 155 [M+H]⁺.

Step 3 Synthesis of tert-butyl5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-carboxylate

The compound (8.10 g) obtained from step 2, platinum oxide (IV), and 10%palladium/carbon (2 g, containing 50% water) were dissolved in methanol(8 mL), and stirred for 34 hours under hydrogen atmosphere of 50 psi(Parr). The reaction solution was filtered through Hyflo Super-Cel. Theoily product obtained by concentrating the solvent was dissolved indichloromethane (200 mL), and added with N,N-diisopropylethylamine (10mL) and di-tert-butyl bicarbonate (11.4 g), followed by stirring for 3hours at room temperature. The reaction solution was added with asaturated aqueous solution of sodium hydrogen carbonate, and extractedthree times with chloroform. The organic layer was dried over sodiumsulfate and concentrated. The obtained residues were purified by silicagel column chromatography to obtain the target compound (2.55 g, 22%).

¹H-NMR (CDCl₃) δ8.15 (1H, s), 4.84 (2H, s), 4.09 (1H, t, J=5.5 Hz), 3.88(1H, t, J=5.5 Hz), 1.50 (9H, s); LRMS (ESI) m/z 225 [M+H]⁺.

Step 4 Synthesis of tert-butyl3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-carboxylate

The compound (1 g) obtained from step 3 was dissolved in chloroform (20mL), and added with sodium hydrogen carbonate (688 mg) andN-bromosuccinimide (873 mg) at 0° C., followed by stirring for 2.5 hoursat room temperature. The reaction solution was added with water, andextracted three times with chloroform. The organic layer was dried oversodium sulfate and concentrated. The obtained residues were purified bysilica gel column chromatography to obtain the target compound (693 mg,51%).

LRMS (ESI) m/z 303 [M+H]⁺.

Step 5 Synthesis of4-(3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (53 mg) obtained from step 4 was dissolved in chloroform (2mL), and added with trifluoroacetic acid (0.2 mL), followed by stirringovernight at room temperature. The oily product obtained byconcentrating the reaction solution under reduced pressure was dissolvedin N,N-dimethylformamide (1.5 mL), and added with cesium carbonate (111mg) and 4-fluoro-2-(trifluoromethyl)benzonitrile (64 mg), followed bystirring at 200° C. for 2 hours. The reaction solution was added withwater, and extracted three times with ethyl acetate. The organic layerwas washed with water and saturated brine, dried over sodium sulfate andconcentrated. The obtained residues were purified by silica gel columnchromatography to obtain the target compound (19 mg, 30%).

LRMS (ESI) m/z 372 [M+H]⁺.

Step 6 Synthesis of4-(3-((4-isopropoxyphenyl)amino)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile

The compound (19 mg) obtained from step 5 was dissolved in dioxane (1mL), and added with 4-isopropoxyaniline (12 mg) and 4 N-hydrochloricacid-dioxane (64 μL), followed by stirring for 20 minutes at 180° C.under microwave irradiation. The reaction solution was added with asaturated aqueous solution of sodium hydrogen carbonate, and extractedthree times with chloroform. The organic layer was dried over sodiumsulfate and concentrated. The obtained residues were purified by silicagel column chromatography to obtain the target compound (13 mg, 57%).

¹H-NMR (CDCl₃) δ7.71 (1H, d, J=8.8 Hz), 7.29 (1H, s), 7.18-7.12 (3H, m),7.03 (1H, dd, J=8.8, 2.7 Hz), 6.88-6.79 (2H, m), 4.66 (2H, s), 4.45 (1H,sept, J=6.1 Hz), 3.83 (4H, br-s), 1.31 (6H, d, J=6.1 Hz); LRMS (ESI) m/z443 [M+H]⁺.

Comparative Example 47-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

Synthesis was performed according to the method described in PatentLiterature 1 or 3.

Comparative Example 53-Chloro-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The compound (74 mg) obtained from step 3 of Example 44,3-chloro-4-fluorobenzonitrile (40 mg), and sodium carbonate (82 mg) wereadded to DMSO (2 mL), and reacted for 3 hours at 120° C. The insolublematters were filtered, and the target compound was obtained by reversephase preparative HPLC column chromatography (26 mg, 24%).

¹H-NMR (DMSO-d6) δ8.92 (1H, s), 8.52 (1H, s), 8.42 (1H, d, J=2.4 Hz),8.07 (1H, d, J=8.8 Hz), 8.01 (1H, d, J=2.4 Hz), 7.84 (1H, dd, J=8.8, 2.4Hz), 7.79 (1H, dd, J=8.4, 2.0 Hz), 7.36 (1H, d, J=8.4 Hz), 5.14 (1H, s),4.26 (2H, s), 3.53 (2H, t, J=5.6 Hz), 2.90 (2H, t, J=5.6 Hz), 1.46 (6H,s); LRMS (ESI) m/z 421 [M+H]⁺

Comparative Example 63-Chloro-5-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The compound (74 mg) obtained from step 3 of Example 44,3-chloro-5-fluorobenzonitrile (40 mg), and sodium carbonate (82 mg) wereadded to DMSO (2 mL), and reacted for 15 hours at 120° C. The insolublematters were filtered, and the target compound was obtained by reversephase preparative HPLC column chromatography (17 mg, yield 15%).

¹H-NMR (DMSO-d6) δ8.99 (1H, s), 8.53 (1H, s), 8.42 (1H, d, J=2.4 Hz),8.04 (1H, d, J=8.4 Hz), 7.83 (1H, dd, J=8.8, 2.8 Hz), 7.51 (1H, s), 7.43(1H, t, J=2.4 Hz), 7.26 (1H, s), 5.13 (1H, s), 4.40 (2H, s), 3.73 (2H,t, J=5.6 Hz), 2.85 (2H, t, J=5.6 Hz), 1.46 (6H, s); LRMS (ESI) m/z 421[M+H]⁺.

Comparative Example 72-Chloro-6-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The compound (74 mg) obtained from step 3 of Example 44,2-chloro-6-fluorobenzonitrile (40 mg), and sodium carbonate (82 mg) wereadded to DMSO (2 mL), and reacted for 3 hours at 120° C. The insolublematters were filtered, and the target compound was obtained by reversephase preparative HPLC column chromatography (18 mg, yield 16%).

¹H-NMR (DMSO-d6) δ9.01 (1H, s), 8.52 (1H, s), 8.43 (1H, d, J=2.4 Hz),8.04 (1H, d, J=8.8 Hz), 7.84 (1H, dd, J=8.8, 2.4 Hz), 7.62 (1H, t, J=8.4Hz), 7.27 (2H, t, J=8.4 Hz), 5.14 (1H, s), 4.31 (2H, s), 3.66 (2H, t,J=5.6 Hz), 2.94 (2H, t, J=5.6 Hz), 1.46 (6H, s); LRMS (ESI) m/z 421[M+H]⁺.

Comparative Example 86-((7-(2-Cyano-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide

Step 1 Synthesis of6-((7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinicacid

The compound (150 mg) obtained from step 1 of Example 44 was suspendedin methanol (1 mL) and 6 mol/L aqueous solution of sodium hydroxide (0.2mL), and under microwave irradiation, reacted for 10 minutes at 120° C.Subsequently, the solid formed by adding 5 N—HCl (0.24 mL) was collectedby filtration and dried to obtain the target product with pale browncolor (120 mg, 83%). It was used for the next reaction without anypurification.

Step 2 Synthesis of6-((7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide

The compound (120 mg) obtained from step 1 was added to DMF (3 mL), andit was further added with DIPEA (N,N-diisopropylethylamine, 76 μL) andHATU (162 mg). Next, 2,2,2-trifluoroethanamine (43 mg) was addedthereto, and the mixture was stirred for 2 hours at room temperature.Subsequently, water (3 mL) was added under ice cooling, followed bystirring for 1 hour. The precipitated solid was collected by filtrationand dried to obtain the target compound (70 mg, yield 92%).

¹H-NMR (DMSO-d6) δ9.28 (1H, s), 9.14 (1H, t, J=6.4 Hz), 8.23 (1H, s),8.54 (1H, s), 8.29 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=8.8 Hz), 7.40-7.30(5H, m), 4.13-4.09 (2H, m), 3.68 (2H, s), 3.46 (2H, s), 2.76-2.72 (4H,m); LRMS (ESI) m/z 443 [M+H]⁺.

Step 3 Synthesis of6-((5,6,7,8-tetrahydropyridopyrodo[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide

The compound (640 mg) obtained from step 2 was dissolved in ethanol (30mL), and added with 10% palladium/carbon (50% wet product, 300 mg),followed by stirring at 70° C. for 5 hours under hydrogen atmosphere.The insoluble matters were removed by Celite, and the filtrate wasconcentrated. The obtained crude product was added with methyl isobutylketone (1 mL) and hexane (1 mL) to precipitate a solid. The solid wascollected by filtration, and dried to obtain the target compound (440mg, yield 86%).

¹H-NMR (DMSO-d6) δ9.16-9.10 (2H, m), 8.80 (1H, s), 8.52 (1H, s), 8.24(1H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 4.13-4.04 (2H, m), 3.71 (2H,s), 2.94 (2H, t, J=5.6 Hz), 2.62-2.60 (2H, m); LRMS (ESI) m/z 353[M+H]⁺.

Step 4 Synthesis of6-((7-(2-cyano-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide

The compound (74 mg) obtained from step3,2-fluoro-5-(trifluoromethyl)benzonitrile (50 mg), sodium carbonate (82mg) were added to DMSO (2 mL), and reacted for 3 hours at 120° C. Theinsoluble matters were filtered, and the target compound was obtained byreverse phase preparative HPLC column chromatography (31 mg, 28%).

¹H-NMR (DMSO-d6) δ9.56 (1H, s), 9.12 (1H, t, J=6.4 Hz), 8.84 (1H, t,J=5.6 Hz), 8.67 (1H, s), 8.30-8.20 (3H, m), 7.61 (1H, d, J=8.8 Hz), 7.48(1H, dd, J=8.8, 2.4 Hz), 6.23 (2H, s), 4.23 (2H, t, J=6.4 Hz), 4.20-4.05(2H, m), 3.23 (2H, t, J=6.4 Hz); LRMS (ESI) m/z 522 [M+H]⁺.

Comparative Example 96-((7-(2-Cyano-5-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide

The compound (74 mg) obtained from step 3 of Comparative Example 8,2-fluoro-4-(trifluoromethyl)benzonitrile (50 mg), and sodium carbonate(82 mg) were added to DMSO (2 mL), and reacted for 3 hours at 120° C.The insoluble matters were filtered, and the target compound wasobtained by reverse phase preparative HPLC column chromatography (32 mg,yield 29%).

¹H-NMR (DMSO-d6) δ9.57 (1H, s), 9.13 (1H, t, J=6.4 Hz), 8.85 (1H, s),8.69 (1H, s), 8.24 (2H, S), 7.94 (1H, d, J=8.0 Hz), 7.87 (1H, s), 7.22(1H, d, J=8.8 Hz), 6.12 (2H, s), 4.26 (2H, t, J=6.4 Hz), 4.18-4.06 (2H,m), 3.24 (2H, t, J=6.4 Hz); LRMS (ESI) m/z 522 [M+H]⁺.

Comparative Example 106-((7-(3-Cyano-2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide

The compound (148 mg) obtained from step 3 of Comparative Example 8,3-fluoro-2-(trifluoromethyl)benzonitrile (100 mg), and sodium carbonate(164 mg) were added to DMSO (2 mL), and reacted for 15 hours at 120° C.The insoluble matters were filtered, and the target compound wasobtained by reverse phase preparative HPLC column chromatography (18 mg,yield 17%).

¹H-NMR (DMSO-d6) δ9.41 (1H, s), 9.14 (1H, t, J=6.4 Hz), 8.86 (1H, d,J=2.4 Hz), 8.62 (1H, s), 8.31 (1H, d, J=8.4 Hz), 8.25 (1H, dd, J=8.8,2.4 Hz), 8.05-8.00 (1H, m), 7.95-7.85 (2H, m), 4.18-4.06 (4H, m), 3.29(2H, t, J=5.6 Hz), 2.92 (2H, t, J=5.6 Hz); LRMS (ESI) m/z 522 [M+H]⁺.

Comparative Example 114-(4-((5-(2-Hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile

The compound (20 mg) obtained from step 3 of Example 44,4-fluorobenzonitrile (11 mg), and potassium carbonate (15 mg) weredissolved in DMSO (0.2 mL), and stirred for 25 minutes at 125° C. underirradiation of microwave. The reaction mixture was purified by reversephase preparative HPLC column chromatography to obtain the targetcompound (4.4 mg, 16%).

¹H-NMR (DMSO-d₆) δ8.67 (1H, s), 8.47 (1H, d, J=8.4 Hz), 8.42 (1H, d,J=2.2 Hz), 7.86 (1H, dd, J=8.8, 2.2 Hz), 7.56 (2H, d, J=9.2 Hz), 6.97(2H, d, J=9.2 Hz), 4.46 (2H, s), 3.82 (2H, t, J=5.7 Hz), 2.82 (2H, t,J=5.7 Hz), 1.62 (6H, s); LRMS (ESI) m/z 387 [M+H]⁺.

Biological Evaluation Test Test Example 1: Antagonist Activity for AR

Antagonist activity for AR was evaluated according to the followingmethod. COS-7 cells (ATCC) were transfected with pMMTV-luc vector(reporter plasmid having, as an androgen response element, murine mousemammary virus long terminal repeat) and pEX-hAR vector (human androgenreceptor expression vector: which expresses human AR gene under controlof CMV promoter) by using Nucleofector (registered trademark) Kit R(Lonza) as a transfection reagent and Amaxa (Lonza). The COS-7 cellsobtained after transfection were seeded in a clear bottom 96 wellmicroplate (BD) at 1.5×10⁴/well with phenol red free RPMI1640 containing10% charcoal-treated fetal bovine serum (hereinbelow, DCC-FBS)(hereinbelow, the medium is referred to as an evaluation medium), andthen cultured overnight. The culture was added with the evaluationmedium containing dihydrotestosterone (DHT) (final concentration of DHT:1 nmol/L) or the evaluation medium containing the compound of Examplesor the compound of Comparative Examples (final concentration of thecompound of Examples or the compound of Comparative Examples: 5, 14, 41,123, 370, 1111, 3333, or 10000 nmol/L), followed by culture for 24hours. Then, the transcription activity value was measured. Thetranscription activity was measured by using Bright-Glo™ LuciferaseAssay System (Promega). From the measured transcription activity, 50%transcription activity inhibition concentration (IC₅₀ value) wascalculated by logistic regression when the transcription activity valueobtained by using 1 nmol/L DHT was 100% and the transcription activityvalue obtained by using the evaluation medium only was 0%.

The results are shown in Table 1. Even when compared with Bicalutamide(Comparative Example 1), the compounds of the present inventionexhibited an antagonist activity for AR equal to or higher than that ofBicalutamide. Meanwhile, the compound of Comparative Example 4 describedin Patent Literatures 1 and 3 exhibited no antagonist activity for AR,which was observed for the compounds of Examples of the presentinvention. Furthermore, unlike the compounds of Examples having5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine skeleton, the compound having5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine skeleton of ComparativeExample 2, the compound having5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine skeleton of ComparativeExample 3, and the compound of Comparative Example 4 described in PatentLiteratures 2 and 3 exhibited no antagonist activity for AR. Inaddition, the compounds described in Comparative Examples 5 to 10 havingcyanobenzene which has a substituent group X but is different from thecompounds of the present invention also did not show the antagonistactivity for AR. Furthermore, the compound described in ComparativeExample 11 not having a substituent group X also did not show theantagonist activity for AR.

TABLE 1

Example X —R IC₅₀ value (μM) 1 CF₃

0.08 2 CF₃

0.37 3 CF₃

0.53 4 CF₃

0.62 5 CF₃

0.19 6 Cl

0.07 7 CF₃

0.16 8 CF₃

0.25 9 Cl

0.25 10 CF₃

0.09 11 CF₃

0.03 12 CF₃

0.17 13 CF₃

0.11 14 CF₃

0.30 15 CF₃

0.13 16 CF₃

0.21 17 CF₃

0.17 18 CF₃

0.36 19 CF₃

0.13 20 CF₃

0.10 21 CF₃

0.38 22 CF₃

0.37 23 CF₃

0.80 24 CF₃

0.07 25 CF₃

3.32 26 CF₃

0.06 27 CF₃

0.09 28 CF₃

0.02 29 Cl

0.2 30 CF₃

ND 31 CF₃

0.39 32 CF₃

0.06 33 CF₃

0.31 34 CF₃

0.70 35 CF₃

0.19 36 CF₃

0.17 37 CF₃

0.17 38 CF₃

0.56 39 CF₃

2.05 40 CF₃

0.26 41 CF₃

1.94 42 CF₃

0 0.34 43 CF₃

0.79 44 Br

0.05 45 Cl

0.94 46 Cl

0.25 47 CF₃

0.07 48 CF₃

0.49 49 Cl

0.002 50 CF₃

0.32 51 CF₃

1.1 52 CF₃

0.15 53 Cl

0.055 54 Cl

NT 55 Cl

NT 56 Cl

0.84 57 CF₃

NT 58 CF₃

NT Comparative Structural formula or IC₅₀ value Example Compound name(μM) 1 Bicalutamide 1.27 2

>10 3

>10 4

>10 5

>10 6

>10 7

>10 8

>10 9

>10 10

>10 11

>10

Test Example 2: Androgen-Dependent Inhibitory Activity on Proliferationof Prostate Cancer Cells

Human prostate cancer cells LNCaP (Non-Patent Literature 5) havingamplified androgen receptor gene were seeded in a clear bottom 96 wellmicroplate (BD) at 4.0×10³/well with phenol red free RPMI1640 containing5% DCC-FBS (hereinbelow, the medium is referred to as an evaluationmedium), and then cultured overnight. The culture was added with theevaluation medium containing DHT (final concentration of DHT: 10 nmol/L)or the evaluation medium containing the compound of Examples or thecompound of Comparative Examples (final concentration of the compound ofExamples or the compound of Comparative Examples: 10, 30, 100, 300,1000, 3000, 10000, or 30000 nmol/L), followed by culture for 72 hours.Then, the number of viable cells was counted. The number of viable cellswas measured by using Cell Counting Kit-8 (DOJINDO LABORATORIES). Fromthe measured number of viable cells, 50% proliferation inhibitionconcentration (GI50 value) was calculated by logistic regression whenthe cell proliferation activity obtained by using 10 nmol/L DHT was 100%and the cell proliferation activity obtained by using the evaluationmedium only was 0%.

The results are shown in Table 2. When compared to Bicalutamide(Comparative Example 1), the compounds of the present inventionexhibited an androgen-dependent inhibitory activity on proliferation ofprostate cancer cells equal to or higher than that of Bicalutamide.

TABLE 2 Example GI₅₀ value (μM) 1 3.0 2 1.0 5 0.6 6 0.4 7 0.5 9 0.5 100.8 11 0.38 13 0.6 14 1.4 16 0.7 17 0.7 18 1.9 19 3.0 20 2.5 23 1.5 243.5 27 2.8 28 3.2 29 0.2 30 3.2 32 3.1 33 2.1 34 3.8 35 1.6 36 0.3 381.1 40 0.4 41 2.4 42 1.1 Comparative 3.5 Example 1

Test Example 3: Agonist Activity for AR

AR positive human prostate cancer cells VCaP (In Vivo 15:163-168, 2001)were seeded in a clear bottom 96 well microplate (BD) at 1.5×10⁴/wellwith phenol red free RPMI1640 containing 5% DCC-FBS (hereinbelow, themedium is referred to as an evaluation medium), and then culturedovernight. The culture was added with the evaluation medium containingthe compound of Examples or the compound of Comparative Examples (finalconcentration of the compound of Examples or the compound of ComparativeExamples: 2, 5, 14, 41, 123, 370, 1111, 3333, or 10000 nmol/L), followedby culture for 72 hours. Then, the number of viable cells was counted(test group). As a control, the cells were cultured after being addedwith the evaluation medium only, and the number of viable cells wascounted (control group). The number of viable cells was measured byusing CellTiter-Glo™ Luminescent Cell Viability Assay (Promega). Fromthe measured number of viable cells, cell proliferation rate withrespect to the compound of Examples or the compound of ComparativeExamples was calculated based on the number of viable cells measured inthe case of using the evaluation medium only.

Cell proliferation rate (%)=(Number of viable cells in test group−Numberof viable cells in control group)/(Number of viable cells in controlgroup)×100

By considering an error in the number of viable cells measured in thecase of using the evaluation medium only, when the cell proliferationrate was more than 10% at any concentration of the 9 concentrationswhich had been evaluated, it was determined to have an agonist activityfor AR.

The results are shown in Table 3. Unlike Bicalutamide (ComparativeExample 1), no agonist activity for AR was observed for the compounds ofthe present invention.

TABLE 3 Cell proliferation Example rate (%) 1 8.7 2 3.8 3 1.0 5 −5.5 6−0.7 7 4.9 9 −0.7 10 2.8 11 2.9 13 2.8 15 0.3 16 −1.5 17 0.6 18 −4.6 200.0 21 −0.6 23 5.1 25 6.3 26 5.7 27 −0.2 32 −2.2 33 4.4 34 6.4 35 0.1 36−1.9 37 0.9 38 −2.7 39 5.5 40 0.0 42 −17.2 44 5.2 46 1.0 47 1.9 48 −2.650 −3.7 51 −5.4 52 −3.4 54 3.4 55 1.0 56 8.0 57 5.0 58 2.0 Comparative39.7 Example 1

Test Example 4: Evaluation of Activity of Reducing Expression Level ofAndrogen Receptor

AR positive human prostate cancer cells LNCaP were seeded in a clearbottom 6 well microplate (BD) at 3.5×10⁵/well with phenol red freeRPMI1640 containing 5% FBS (hereinbelow, the medium is referred to as anevaluation medium), and then cultured overnight. The culture was addedwith the evaluation medium containing the compound of Examples or thecompound of Comparative Examples such that the final concentration ofthe compound of Examples or the compound of Comparative Examples was10000 nmol/L, followed by culture for 48 hours. After culture for 48hours, the medium was removed and the cells were washed with PBS andadded with 0.1 mL of Lysis buffer (M-PER added with Protease InhibitorCocktail), followed by keeping at 4° C. for 20 minutes. After celllysis, the cell solution was centrifuged to recover the supernatant ascell lysate. The cell lysates were adjusted to have the same proteinconcentration and subjected to SDS-PAGE and Western blotting using antiAR antibody (Santa Cruz Biotechnology, N-20). The antibody-reacting band(anti AR receptor) was quantified by LAS-3000 (FUJIFILM) using SuperSignal West Pico Substrate (Thermo Scientific) as a detection reagent.For the quantification, when the AR expression in LNCaP was reduced by50% or more compared with the evaluation medium control, it wasdetermined to have an AR expression inhibitory activity.

The results are shown in Table 4. When the AR expression reducingactivity is 50% or more, it is described as “reduced”. For ComparativeExamples 1 to 4, the AR expression reducing activity was less than 10%at 10 μM, and thus the activity was not observed at all. In contrast,the compounds of the present invention were confirmed to have ARexpression reducing activity of 50% or more at 10 μM.

TABLE 4 10 μM AR expression reducing Example activity 1 reduced 2reduced 3 reduced 4 reduced 5 reduced 6 reduced 7 reduced 8 reduced 9reduced 10 reduced 11 reduced 12 reduced 13 reduced 14 reduced 16reduced 17 reduced 18 reduced 20 reduced 24 reduced 26 reduced 28reduced 30 reduced 32 reduced 34 reduced 36 reduced 37 reduced 38reduced 39 reduced 40 reduced 41 reduced 42 reduced 44 reduced 46reduced 47 reduced 49 reduced 50 reduced 51 reduced 52 reduced 57reduced Comparative <10% Example 1 Comparative <10% Example 2Comparative <10% Example 3 Comparative <10% Example 4

Test Example 5: Evaluation of Anti-Tumor Activity in In Vivo Model ofCastration Resistant Prostate Cancer

From the AR positive human prostate cancer cells LNCaP, castrationresistant prostate cancer cells, LNCaP-Xeno-IL-6 cells, were establishedbased on the scientific paper (Clin Cancer Res, 2001 7:2941-8) (in thepaper, the cells have been reported as LNCaP-IL-6+ cells) and used forthe in vivo test. The LNCaP-Xeno-IL-6 cells were implantedsubcutaneously in male nude mice, and the castration treatment wasperformed when the tumor volume reached about 200 mm³. After thecastration, the vehicle only (0.5% HPMC) or the compound of Examplessuspended in the vehicle was orally administered to the mice every dayfor 2 weeks. The compound of Examples was administered such that therewas no difference in an exposure amount between the compounds. After theadministration for 2 weeks, the tumor volume of each mouse was recordedand the average tumor volume of the group administered with theevaluation compound relative to the average tumor volume of the groupadministered only with the vehicle, that is, T/C (%), was calculatedbased on the following formula.

T/C (%)=(Average tumor volume of evaluation compound group)/(Averagetumor volume of vehicle administration group)

The results are shown in Table 5. The compounds of the present inventionexhibited an anti-tumor effect in an in vivo model of castrationresistant prostate cancer.

TABLE 5 Daily dose Example (mg/kg/day) T/C (%) 6 100 29 7 30 49 9 15 4011 200 47

1-22. (canceled) 23: A method for inhibiting androgen activity,comprising: administering an effective amount of atetrahydropyridopyrimidine compound of formula (I) or a pharmaceuticallyacceptable salt thereof to a subject in need thereof,

wherein, in the formula (I), X is a halogen atom or a halogeno-C₁₋₃alkyl group; R is a C₆₋₁₄ aryl group which is substituted with R¹ and issimultaneously substituted or unsubstituted with R², or a 5- or6-membered heteroaryl group which is substituted with R¹ and issimultaneously substituted or unsubstituted with R²; R¹ is a hydrogenatom, a phenyl group, a hydroxy-C₁₋₆ alkyl group, a hydroxy-C₃₋₇cycloalkyl group, a C₁₋₆ alkoxy group which is substituted orunsubstituted with Ra, a C₃₋₇ cycloalkylaminosulfonyl group, a 3- to7-membered monocyclic heterocycloalkylsulfonyl group, a halogeno-C₁₋₃alkoxycarbonylamino group, a halogeno-C₁₋₃ alkylcarbonylamino group, a3- to 7-membered monocyclic heterocycloalkanecarbonyl group substitutedwith a hydroxy-C₁₋₆ alkyl group, or —(CH₂)_(n)—C(═O)—NHRf; R² is ahydrogen atom, a halogen atom, or a halogeno-C₁₋₃ alkyl group; Ra is aC₁₋₆ alkylpyrazolyl group, a triazolyl group, a tetrazolyl group, or aC₁₋₆ alkylsulfonylpiperazinyl group; Rf is a halogeno-C₁₋₃ alkyl group,a hydroxy-C₁₋₆ alkyl group, a hydroxy-C₃₋₇ cycloalkyl group, ahydroxy-C₃₋₇ cycloalkyl-C₁₋₆ alkyl group, or a C₁₋₆ alkyl groupsubstituted with Rfa; Rfa is a C₁₋₆ alkylpyrazolyl group, ahalogeno-C₁₋₃ alkylthiazolyl group, an oxadiazolyl group, or ahalogeno-C₁₋₃ alkyloxadiazolyl group; and n is an integer of from 0 to3. 24: The method of claim 23, wherein, in the formula (I), X is achlorine atom, a bromine atom, or a trifluoromethyl group. 25: Themethod of claim 23, wherein, in the formula (I), n is 0 or
 1. 26: Themethod of claim 23, wherein, in the formula (I), R is selected from thegroup consisting of:

27: The method of claim 23, wherein, in the formula (I), R¹ is ahydrogen atom, a phenyl group, a hydroxy-ethyl group, ahydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, a methoxy group, an isopropoxy group, anethoxy group substituted with a methylpyrazolyl group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, an n-propoxy group substituted with amethylsulfonylpiperazinyl group, a cyclopropylaminosulfonyl group, a1,4-oxazepanylsulfonyl group, a 2,2,2-trifluoroethoxycarbonylaminogroup, a 2,2,2-trifluoroethylcarbonylamino group, a piperidinecarbonylgroup substituted with a hydroxy-isopropyl group, or—(CH₂)_(n)—C(═O)—NHRf; Rf is a 2,2-difluoroethyl group, a2,2,2-trifluoroethyl group, a hydroxy-2-methylpropyl group, ahydroxycyclohexyl group, a hydroxycyclopropylmethyl group, a methylgroup substituted with a trifluoromethylthiazolyl group, an ethyl groupsubstituted with a methylthiazolyl group, an ethyl group substitutedwith an oxadiazolyl group, or an ethyl group substituted with atrifluoromethyloxazolyl group; and n is 0 or
 1. 28: The method of claim23, wherein, in the formula (I), R is selected from the group consistingof:

where R¹ is a hydrogen atom;

where R¹ is —(CH₂)_(n)—C(═O)—NHRf, Rf is a methyl group substituted withRfa or an ethyl group substituted with Rfa, Rfa is a methylpyrazolylgroup or an oxadiazolyl group, and n is 0;

where R¹ is a phenyl group, a hydroxy-ethyl group, a hydroxy-isopropylgroup, a methoxy group, an isopropoxy group, an ethoxy group substitutedwith a methylpyrazolyl group, or an n-propoxy group substituted with amethylsulfonylpiperazinyl group;

where R¹ is a hydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, an isopropoxy group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, a cyclopropylaminosulfonyl group, a2,2,2-trifluoroethoxycarbonylamino group, a2,2,2-trifluoroethylcarbonylamino group, or —(CH₂)_(n)—C(═O)—NHRf, R² isa hydrogen atom, a fluorine atom, or a chlorine atom, Rf is a2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a methyl groupsubstituted with Rfa, or an ethyl group substituted with Rfa, Rfa is atrifluoromethylthiazolyl group, an oxadiazolyl group, or atrifluoromethyloxadiazolyl group, and n is 0 or 1;

where R¹ is a hydroxy-isopropyl group, a 1,4-oxazepanylsulfonyl group,or —(CH₂)_(n)—C(═O)—NHRf, R² is a hydrogen atom or a trifluoromethylgroup, Rf is a 2,2,2-trifluoroethyl group or an ethyl group substitutedwith Rfa, Rfa is an oxadiazolyl group, and n is 0;

where R¹ is a hydroxy-isopropyl group or —(CH₂)_(n)—C(═O)—NHRf, Rf is a2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a hydroxycyclohexyl group, ahydroxycyclopropylmethyl group, and n is 0;

where R¹ is —(CH₂)_(n)—C(═O)—NHRf, Rf is a hydroxy-2-methylpropyl group,and n is 0;

where R¹ is —(CH₂)_(n)—C(═O)—NHRf, Rf is a hydroxy-2-methylpropyl group,and n is 0;

where R¹ is —(CH₂)_(n)—C(═O)—NHRf, Rf is a 2,2,2-trifluoroethyl group,and n is 0;

where R¹ is a piperidinecarbonyl group substituted with ahydroxy-isopropyl group; and

where R¹ is a piperidinecarbonyl group substituted with ahydroxy-isopropyl group. 29: The method of claim 23, wherein, in theformula (I), X is a chlorine atom, a bromine atom, or a trifluoromethylgroup, and R is selected from the group consisting of:

where R¹ is a hydrogen atom, a phenyl group, a hydroxy-C₁₋₄ alkyl group,a hydroxy-C₃₋₅ cycloalkyl group, a C₁₋₄ alkoxy group which issubstituted or unsubstituted with Ra, a C₃₋₅ cycloalkylaminosulfonylgroup, a 7-membered monocyclic heterocycloalkylsulfonyl group, afluoro-C₁₋₃ alkoxycarbonylamino group, a fluoro-C₁₋₃ alkylcarbonylaminogroup, a 6-membered monocyclic heterocycloalkanecarbonyl groupsubstituted with a hydroxy-C₁₋₄ alkyl group, or —(CH₂)_(n)—C(═O)—NHRf,R² is a hydrogen atom, a fluorine atom, a chlorine atom, or atrifluoromethyl group; Ra is a C₁₋₄ alkylpyrazolyl group, a triazolylgroup, a tetrazolyl group, or a C₁₋₄ alkylsulfonylpiperazinyl group, Rfis a fluoro-C₁₋₃ alkyl group, a hydroxy-C₁₋₄ alkyl group, a hydroxy-C₃₋₅cycloalkyl group, a hydroxy-C₃₋₅ cycloalkyl-C₁₋₄ alkyl group, or a C₁₋₄alkyl group substituted with Rfa, Rfa is a C₁₋₄ alkylpyrazolyl group, afluoro-C₁₋₃ alkylthiazolyl group, an oxadiazolyl group, or a fluoro-C₁₋₃alkyloxadiazolyl group, and n is 0 or
 1. 30: The method of claim 29,wherein, in the formula (I), R is selected from the group consisting of:

where R¹ is a hydrogen atom, a phenyl group, a hydroxy-ethyl group, ahydroxy-isopropyl group, a hydroxy-cyclopropyl group, ahydroxy-cyclobutyl group, a methoxy group, an isopropoxy group, anethoxy group substituted with a methylpyrazolyl group, an ethoxy groupsubstituted with a triazolyl group, a 2-methylpropoxy group substitutedwith a triazolyl group, a 2-methylpropoxy group substituted with atetrazolyl group, an n-propoxy group substituted with amethylsulfonylpiperazinyl group, a cyclopropylaminosulfonyl group, a1,4-oxazepanylsulfonyl group, a 2,2,2-trifluoroethoxycarbonylaminogroup, a 2,2,2-trifluoroethylcarbonylamino group, a piperidinecarbonylgroup substituted with a hydroxy-isopropyl group, or—(CH₂)_(n)—C(═O)—NHRf, R² is a hydrogen atom, a fluorine atom, achlorine atom, or a trifluoromethyl group; Rf is a 2,2-difluoroethylgroup, a 2,2,2-trifluoroethyl group, a hydroxy-2-methylpropyl group, ahydroxycyclohexyl group, a hydroxycyclopropylmethyl group, a methylgroup substituted with a trifluoromethylthiazolyl group, an ethyl groupsubstituted with a methylthiazolyl group, an ethyl group substitutedwith an oxadiazolyl group, or an ethyl group substituted with atrifluoromethyl group, and n is 0 or
 1. 31: The method of claim 30,wherein, in the formula (I), X is a chlorine atom or a trifluoromethylgroup, and R is selected from the group consisting of:

where R¹ is a hydrogen atom, a hydroxy-isopropyl group, an isopropoxygroup, a 2-methylpropoxy group substituted with a tetrazolyl group, ann-propoxy group substituted with a methylsulfonylpiperazinyl group, a1,4-oxazepanylsulfonyl group, a piperidinecarbonyl group substitutedwith a hydroxy-isopropyl group, or —(CH₂)_(n)—C(═O)—NHRf, R² is ahydrogen atom or a fluorine atom, Rf is a 2,2,2-trifluoroethyl group, ahydroxy-2-methylpropyl group, a methyl group substituted with atrifluoromethylthiazolyl group, an ethyl group substituted with anoxadiazolyl group, or an ethyl group substituted with atrifluoromethyloxadiazolyl group, and n is
 0. 32: The method of claim23, wherein the tetrahydropyridopyrimidine compound is at least oneselected from the group consisting of: (1)4-(4-((1,2,4-thiadiazol-5-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(2)4-(4-((4-isopropoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(3)4-(4-((6-fluoro-5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(4)2-chloro-4-(4-((6-(2-hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile;(5)4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(6)2-chloro-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile;(7)4-(4-((6-(2-hydroxypropan-2-yl)pyridazin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(8)6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8,-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)nicotinamide;(9)4-(4-((6-isopropoxypyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(10)4-(4-((6-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-3-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(11)4-(4-((5-(2-methyl-2-(1H-tetrazol-1-yl)propoxy)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(12) 4-(4-((4-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(13)4-(4-((5-((1,4-oxazepan-4-yl)sulfonyl)thiazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;(14)6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyridazine-3-carboxamide;(15)2-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyrimidine-5-carboxamide;(16)6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-((4-(trifluoromethyl)thiazol-2-yl)methyl)nicotinamide;(17)(R)—N-(1-(1,3,4-oxadiazol-2-yl)ethyl)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinamide;(18)(R)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethyl)nicotinamide;and (19)4-(4-((5-(4-(2-hydroxypropan-2-yl)piperidin-1-carbonyl)oxazol-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile.33: The method of claim 23, wherein the subject has at least one tumorselected from the group consisting of prostate cancer, breast cancer,ovarian cancer, bladder cancer, uterine cancer, pancreatic cancer, andhepatocellular cancer. 34: The method of claim 32, wherein the subjecthas at least one tumor selected from the group consisting of prostatecancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer,pancreatic cancer, and hepatocellular cancer. 35: The method of claim23, wherein the subject has prostate cancer. 36: The method of claim 35,wherein the prostate cancer is at least one selected from the groupconsisting of castration resistant prostate cancer, hormone resistantprostate cancer, PSA recurrent prostate cancer, taxan resistant prostatecancer, and radiation resistant prostate cancer. 37: The method of claim23, wherein the subject has breast cancer. 38: The method of claim 23,wherein the tetrahydropyridopyrimidine compound or the pharmaceuticallyacceptable salt thereof is orally administered to the subject. 39: Themethod of claim 23, wherein the tetrahydropyridopyrimidine compound orthe pharmaceutically acceptable salt thereof is administered to thesubject in an amount of 0.05 to 5,000 mg per day. 40: The method ofclaim 23, wherein the tetrahydropyridopyrimidine compound or thepharmaceutically acceptable salt thereof is administered to the subjectonce, twice, three times, or four times a day. 41: The method of claim32, wherein the subject has at least one tumor selected from the groupconsisting of prostate cancer, breast cancer, ovarian cancer, bladdercancer, uterine cancer, pancreatic cancer, and hepatocellular cancer,and the tetrahydropyridopyrimidine compound or the pharmaceuticallyacceptable salt thereof is orally administered to the subject.